RBCC Red Blood Cell Collection

TNF (TNFA, TNFSF2) [Confidence: low (only semi-automatic identification from reviews)]
Tumor necrosis factor (Cachectin; TNF-alpha; Tumor necrosis factor ligand superfamily member 2; TNF-a; Tumor necrosis factor, membrane form; N-terminal fragment; NTF; Intracellular domain 1; ICD1; Intracellular domain 2; ICD2; C-domain 1; C-domain 2; Tumor necrosis factor, soluble form; Flags: Precursor)

UniProt P01375
ID TNFA_HUMAN Reviewed; 233 AA.
AC P01375; O43647; Q9P1Q2; Q9UIV3;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 21-JUL-1986, sequence version 1.
DT 22-JAN-2014, entry version 190.
DE RecName: Full=Tumor necrosis factor;
DE AltName: Full=Cachectin;
DE AltName: Full=TNF-alpha;
DE AltName: Full=Tumor necrosis factor ligand superfamily member 2;
DE Short=TNF-a;
DE Contains:
DE RecName: Full=Tumor necrosis factor, membrane form;
DE AltName: Full=N-terminal fragment;
DE Short=NTF;
DE Contains:
DE RecName: Full=Intracellular domain 1;
DE Short=ICD1;
DE Contains:
DE RecName: Full=Intracellular domain 2;
DE Short=ICD2;
DE Contains:
DE RecName: Full=C-domain 1;
DE Contains:
DE RecName: Full=C-domain 2;
DE Contains:
DE RecName: Full=Tumor necrosis factor, soluble form;
DE Flags: Precursor;
GN Name=TNF; Synonyms=TNFA, TNFSF2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=3555974;
RA Nedospasov S.A., Shakhov A.N., Turetskaya R.L., Mett V.A.,
RA Azizov M.M., Georgiev G.P., Korobko V.G., Dobrynin V.N.,
RA Filippov S.A., Bystrov N.S., Boldyreva E.F., Chuvpilo S.A.,
RA Chumakov A.M., Shingarova L.N., Ovchinnikov Y.A.;
RT "Tandem arrangement of genes coding for tumor necrosis factor (TNF-
RT alpha) and lymphotoxin (TNF-beta) in the human genome.";
RL Cold Spring Harb. Symp. Quant. Biol. 51:611-624(1986).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RX PubMed=6392892; DOI=10.1038/312724a0;
RA Pennica D., Nedwin G.E., Hayflick J.S., Seeburg P.H., Derynck R.,
RA Palladino M.A., Kohr W.J., Aggarwal B.B., Goeddel D.V.;
RT "Human tumour necrosis factor: precursor structure, expression and
RT homology to lymphotoxin.";
RL Nature 312:724-729(1984).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RX PubMed=3883195; DOI=10.1038/313803a0;
RA Shirai T., Yamaguchi H., Ito H., Todd C.W., Wallace R.B.;
RT "Cloning and expression in Escherichia coli of the gene for human
RT tumour necrosis factor.";
RL Nature 313:803-806(1985).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RX PubMed=2995927; DOI=10.1093/nar/13.17.6361;
RA Nedwin G.E., Naylor S.L., Sakaguchi A.Y., Smith D.H.,
RA Jarrett-Nedwin J., Pennica D., Goeddel D.V., Gray P.W.;
RT "Human lymphotoxin and tumor necrosis factor genes: structure,
RT homology and chromosomal localization.";
RL Nucleic Acids Res. 13:6361-6373(1985).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=3856324; DOI=10.1126/science.3856324;
RA Wang A.M., Creasey A.A., Ladner M.B., Lin L.S., Strickler J.,
RA van Arsdell J.N., Yamamoto R., Mark D.F.;
RT "Molecular cloning of the complementary DNA for human tumor necrosis
RT factor.";
RL Science 228:149-154(1985).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=3932069; DOI=10.1111/j.1432-1033.1985.tb09226.x;
RA Marmenout A., Fransen L., Tavernier J., van der Heyden J., Tizard R.,
RA Kawashima E., Shaw A., Johnson M.J., Semon D., Mueller R.,
RA Ruysschaert M.-R., van Vliet A., Fiers W.;
RT "Molecular cloning and expression of human tumor necrosis factor and
RT comparison with mouse tumor necrosis factor.";
RL Eur. J. Biochem. 152:515-522(1985).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=8499947; DOI=10.1038/ng0293-137;
RA Iris F.J.M., Bougueleret L., Prieur S., Caterina D., Primas G.,
RA Perrot V., Jurka J., Rodriguez-Tome P., Claverie J.-M., Dausset J.,
RA Cohen D.;
RT "Dense Alu clustering and a potential new member of the NF kappa B
RT family within a 90 kilobase HLA class III segment.";
RL Nat. Genet. 3:137-145(1993).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=10202016;
RA Neville M.J., Campbell R.D.;
RT "A new member of the Ig superfamily and a V-ATPase G subunit are among
RT the predicted products of novel genes close to the TNF locus in the
RT human MHC.";
RL J. Immunol. 162:4745-4754(1999).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=14656967; DOI=10.1101/gr.1736803;
RA Xie T., Rowen L., Aguado B., Ahearn M.E., Madan A., Qin S.,
RA Campbell R.D., Hood L.;
RT "Analysis of the gene-dense major histocompatibility complex class III
RT region and its comparison to mouse.";
RL Genome Res. 13:2621-2636(2003).
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Shiina S., Tamiya G., Oka A., Inoko H.;
RT "Homo sapiens 2,229,817bp genomic DNA of 6p21.3 HLA class I region.";
RL Submitted (SEP-1999) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Shiina T., Ota M., Katsuyama Y., Hashimoto N., Inoko H.;
RT "Genome diversity in HLA: a new strategy for detection of genetic
RT polymorphisms in expressed genes within the HLA class III and class I
RT regions.";
RL Submitted (JUL-2002) to the EMBL/GenBank/DDBJ databases.
RN [12]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG SeattleSNPs variation discovery resource;
RL Submitted (DEC-2001) to the EMBL/GenBank/DDBJ databases.
RN [13]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT LEU-84.
RG NIEHS SNPs program;
RL Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases.
RN [14]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Blood;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [15]
RP PROTEIN SEQUENCE OF 77-99, AND GLYCOSYLATION AT SER-80.
RX PubMed=8631363; DOI=10.1111/j.1432-1033.1996.00431.x;
RA Takakura-Yamamoto R., Yamamoto S., Fukuda S., Kurimoto M.;
RT "O-glycosylated species of natural human tumor-necrosis factor-
RT alpha.";
RL Eur. J. Biochem. 235:431-437(1996).
RN [16]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 77-233.
RA Jang J.S., Kim B.E.;
RL Submitted (JAN-1998) to the EMBL/GenBank/DDBJ databases.
RN [17]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 84-214.
RC TISSUE=Prostatic carcinoma;
RA Shao C., Yan W., Zhu F., Yue W., Chai Y., Zhao Z., Wang C.;
RL Submitted (MAR-2000) to the EMBL/GenBank/DDBJ databases.
RN [18]
RP PHOSPHORYLATION (MEMBRANE FORM).
RX PubMed=8597870;
RA Pocsik E., Duda E., Wallach D.;
RT "Phosphorylation of the 26 kDa TNF precursor in monocytic cells and in
RT transfected HeLa cells.";
RL J. Inflamm. 45:152-160(1995).
RN [19]
RP PHOSPHORYLATION BY CK1, AND DEPHOSPHORYLATION.
RX PubMed=10205166; DOI=10.1093/emboj/18.8.2119;
RA Watts A.D., Hunt N.H., Wanigasekara Y., Bloomfield G., Wallach D.,
RA Roufogalis B.D., Chaudhri G.;
RT "A casein kinase I motif present in the cytoplasmic domain of members
RT of the tumour necrosis factor ligand family is implicated in 'reverse
RT signalling'.";
RL EMBO J. 18:2119-2126(1999).
RN [20]
RP MUTAGENESIS.
RX PubMed=2009860;
RA Ostade X.V., Tavernier J., Prange T., Fiers W.;
RT "Localization of the active site of human tumour necrosis factor
RT (hTNF) by mutational analysis.";
RL EMBO J. 10:827-836(1991).
RN [21]
RP MYRISTOYLATION AT LYS-19 AND LYS-20.
RX PubMed=1402651; DOI=10.1084/jem.176.4.1053;
RA Stevenson F.T., Bursten S.L., Locksley R.M., Lovett D.H.;
RT "Myristyl acylation of the tumor necrosis factor alpha precursor on
RT specific lysine residues.";
RL J. Exp. Med. 176:1053-1062(1992).
RN [22]
RP CLEAVAGE BY ADAM17.
RX PubMed=9034191; DOI=10.1038/385733a0;
RA Moss M.L., Jin S.-L.C., Milla M.E., Burkhart W., Carter H.L.,
RA Chen W.-J., Clay W.C., Didsbury J.R., Hassler D., Hoffman C.R.,
RA Kost T.A., Lambert M.H., Leesnitzer M.A., McCauley P., McGeehan G.,
RA Mitchell J., Moyer M., Pahel G., Rocque W., Overton L.K., Schoenen F.,
RA Seaton T., Su J.-L., Warner J., Willard D., Becherer J.D.;
RT "Cloning of a disintegrin metalloproteinase that processes precursor
RT tumour-necrosis factor-alpha.";
RL Nature 385:733-736(1997).
RN [23]
RP POLYMORPHISM, AND INVOLVEMENT IN SUSCEPTIBILITY TO MALARIA.
RX PubMed=10369255; DOI=10.1038/9649;
RA Knight J.C., Udalova I., Hill A.V., Greenwood B.M., Peshu N.,
RA Marsh K., Kwiatkowski D.;
RT "A polymorphism that affects OCT-1 binding to the TNF promoter region
RT is associated with severe malaria.";
RL Nat. Genet. 22:145-150(1999).
RN [24]
RP FUNCTION OF TNF INTRACELLULAR DOMAIN, CLEAVAGE BY SPPL2A AND SPPL2B,
RP AND SUBCELLULAR LOCATION.
RX PubMed=16829952; DOI=10.1038/ncb1440;
RA Friedmann E., Hauben E., Maylandt K., Schleeger S., Vreugde S.,
RA Lichtenthaler S.F., Kuhn P.H., Stauffer D., Rovelli G., Martoglio B.;
RT "SPPL2a and SPPL2b promote intramembrane proteolysis of TNFalpha in
RT activated dendritic cells to trigger IL-12 production.";
RL Nat. Cell Biol. 8:843-848(2006).
RN [25]
RP CLEAVAGE BY SPPL2A AND SPPL2B, CLEAVAGE SITE, INTERACTION WITH SPPL2B,
RP AND IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=16829951; DOI=10.1038/ncb1450;
RA Fluhrer R., Grammer G., Israel L., Condron M.M., Haffner C.,
RA Friedmann E., Bohland C., Imhof A., Martoglio B., Teplow D.B.,
RA Haass C.;
RT "A gamma-secretase-like intramembrane cleavage of TNFalpha by the GxGD
RT aspartyl protease SPPL2b.";
RL Nat. Cell Biol. 8:894-896(2006).
RN [26]
RP X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS).
RX PubMed=2922050; DOI=10.1038/338225a0;
RA Jones E.Y., Stuart D.I., Walker N.P.;
RT "Structure of tumour necrosis factor.";
RL Nature 338:225-228(1989).
RN [27]
RP X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS).
RX PubMed=1964681;
RA Jones E.Y., Stuart D.I., Walker N.P.;
RT "The structure of tumour necrosis factor -- implications for
RT biological function.";
RL J. Cell Sci. Suppl. 13:11-18(1990).
RN [28]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS).
RX PubMed=2551905;
RA Eck M.J., Sprang S.R.;
RT "The structure of tumor necrosis factor-alpha at 2.6-A resolution.
RT Implications for receptor binding.";
RL J. Biol. Chem. 264:17595-17605(1989).
RN [29]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF MUTANT ARG-107.
RX PubMed=9488135; DOI=10.1093/protein/10.10.1101;
RA Reed C., Fu Z.Q., Wu J., Xue Y.N., Harrison R.W., Chen M.J.,
RA Weber I.T.;
RT "Crystal structure of TNF-alpha mutant R31D with greater affinity for
RT receptor R1 compared with R2.";
RL Protein Eng. 10:1101-1107(1997).
RN [30]
RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF MUTANT SER-3.
RX PubMed=9442056; DOI=10.1074/jbc.273.4.2153;
RA Cha S.S., Kim J.S., Cho H.S., Shin N.K., Jeong W., Shin H.C.,
RA Kim Y.J., Hahn J.H., Oh B.H.;
RT "High resolution crystal structure of a human tumor necrosis factor-
RT alpha mutant with low systemic toxicity.";
RL J. Biol. Chem. 273:2153-2160(1998).
RN [31]
RP INVOLVEMENT IN PSORIATIC ARTHRITIS SUSCEPTIBILITY.
RX PubMed=12746914; DOI=10.1002/art.10935;
RA Balding J., Kane D., Livingstone W., Mynett-Johnson L., Bresnihan B.,
RA Smith O., FitzGerald O.;
RT "Cytokine gene polymorphisms: association with psoriatic arthritis
RT susceptibility and severity.";
RL Arthritis Rheum. 48:1408-1413(2003).
RN [32]
RP INVOLVEMENT IN SUSCEPTIBILITY TO HBV INFECTION.
RX PubMed=12915457; DOI=10.1093/hmg/ddg262;
RA Kim Y.J., Lee H.-S., Yoon J.-H., Kim C.Y., Park M.H., Kim L.H.,
RA Park B.L., Shin H.D.;
RT "Association of TNF-alpha promoter polymorphisms with the clearance of
RT hepatitis B virus infection.";
RL Hum. Mol. Genet. 12:2541-2546(2003).
CC -!- FUNCTION: Cytokine that binds to TNFRSF1A/TNFR1 and
CC TNFRSF1B/TNFBR. It is mainly secreted by macrophages and can
CC induce cell death of certain tumor cell lines. It is potent
CC pyrogen causing fever by direct action or by stimulation of
CC interleukin-1 secretion and is implicated in the induction of
CC cachexia, Under certain conditions it can stimulate cell
CC proliferation and induce cell differentiation.
CC -!- FUNCTION: The TNF intracellular domain (ICD) form induces IL12
CC production in dendritic cells.
CC -!- SUBUNIT: Homotrimer. Interacts with SPPL2B.
CC -!- INTERACTION:
CC Q8UYL3:crmE (xeno); NbExp=3; IntAct=EBI-359977, EBI-7539950;
CC Q9Y6K9:IKBKG; NbExp=2; IntAct=EBI-359977, EBI-81279;
CC P19438:TNFRSF1A; NbExp=7; IntAct=EBI-359977, EBI-299451;
CC -!- SUBCELLULAR LOCATION: Cell membrane; Single-pass type II membrane
CC protein.
CC -!- SUBCELLULAR LOCATION: Tumor necrosis factor, membrane form:
CC Membrane; Single-pass type II membrane protein.
CC -!- SUBCELLULAR LOCATION: Tumor necrosis factor, soluble form:
CC Secreted.
CC -!- SUBCELLULAR LOCATION: C-domain 1: Secreted.
CC -!- SUBCELLULAR LOCATION: C-domain 2: Secreted.
CC -!- PTM: The soluble form derives from the membrane form by
CC proteolytic processing. The membrane-bound form is further
CC proteolytically processed by SPPL2A or SPPL2B through regulated
CC intramembrane proteolysis producing TNF intracellular domains
CC (ICD1 and ICD2) released in the cytosol and TNF C-domain 1 and C-
CC domain 2 secreted into the extracellular space.
CC -!- PTM: The membrane form, but not the soluble form, is
CC phosphorylated on serine residues. Dephosphorylation of the
CC membrane form occurs by binding to soluble TNFRSF1A/TNFR1.
CC -!- PTM: O-glycosylated; glycans contain galactose, N-
CC acetylgalactosamine and N-acetylneuraminic acid.
CC -!- POLYMORPHISM: Genetic variations in TNF influence susceptibility
CC to hepatitis B virus (HBV) infection [MIM:610424].
CC -!- POLYMORPHISM: Genetic variations in TNF are involved in
CC susceptibility to malaria [MIM:611162].
CC -!- DISEASE: Psoriatic arthritis (PSORAS) [MIM:607507]: An
CC inflammatory, seronegative arthritis associated with psoriasis. It
CC is a heterogeneous disorder ranging from a mild, non-destructive
CC disease to a severe, progressive, erosive arthropathy. Five types
CC of psoriatic arthritis have been defined: asymmetrical
CC oligoarthritis characterized by primary involvement of the small
CC joints of the fingers or toes; asymmetrical arthritis which
CC involves the joints of the extremities; symmetrical polyarthritis
CC characterized by a rheumatoid like pattern that can involve hands,
CC wrists, ankles, and feet; arthritis mutilans, which is a rare but
CC deforming and destructive condition; arthritis of the sacroiliac
CC joints and spine (psoriatic spondylitis). Note=Disease
CC susceptibility is associated with variations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the tumor necrosis factor family.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAF71992.1; Type=Frameshift; Positions=91, 157;
CC Sequence=CAA75070.1; Type=Erroneous gene model prediction;
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Tumor necrosis factor alpha
CC entry;
CC URL="http://en.wikipedia.org/wiki/Tumor_necrosis_factor-alpha";
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/TNFaID319.html";
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/tnf/";
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/tnf/";
CC -!- WEB RESOURCE: Name=SHMPD; Note=The Singapore human mutation and
CC polymorphism database;
CC URL="http://shmpd.bii.a-star.edu.sg/gene.php?genestart=A&genename;=TNF";
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DR EMBL; M16441; AAA61200.1; -; Genomic_DNA.
DR EMBL; X02910; CAA26669.1; -; Genomic_DNA.
DR EMBL; X01394; CAA25650.1; -; mRNA.
DR EMBL; M10988; AAA61198.1; -; mRNA.
DR EMBL; M26331; AAA36758.1; -; Genomic_DNA.
DR EMBL; Z15026; CAA78745.1; -; Genomic_DNA.
DR EMBL; Y14768; CAA75070.1; ALT_SEQ; Genomic_DNA.
DR EMBL; AF129756; AAD18091.1; -; Genomic_DNA.
DR EMBL; BA000025; BAB63396.1; -; Genomic_DNA.
DR EMBL; AB088112; BAC54944.1; -; Genomic_DNA.
DR EMBL; AY066019; AAL47581.1; -; Genomic_DNA.
DR EMBL; AY214167; AAO21132.1; -; Genomic_DNA.
DR EMBL; BC028148; AAH28148.1; -; mRNA.
DR EMBL; AF043342; AAC03542.1; -; mRNA.
DR EMBL; AF098751; AAF71992.1; ALT_FRAME; mRNA.
DR PIR; A93585; QWHUN.
DR RefSeq; NP_000585.2; NM_000594.3.
DR UniGene; Hs.241570; -.
DR PDB; 1A8M; X-ray; 2.30 A; A/B/C=77-233.
DR PDB; 1TNF; X-ray; 2.60 A; A/B/C=77-233.
DR PDB; 2AZ5; X-ray; 2.10 A; A/B/C/D=86-233.
DR PDB; 2E7A; X-ray; 1.80 A; A/B/C=77-233.
DR PDB; 2TUN; X-ray; 3.10 A; A/B/C/D/E/F=77-233.
DR PDB; 2ZJC; X-ray; 2.50 A; A/B/C=77-233.
DR PDB; 2ZPX; X-ray; 2.83 A; A/B/C=77-233.
DR PDB; 3ALQ; X-ray; 3.00 A; A/B/C/D/E/F=77-233.
DR PDB; 3IT8; X-ray; 2.80 A; A/B/C/G/H/I=82-233.
DR PDB; 3L9J; X-ray; 2.10 A; T=85-233.
DR PDB; 3WD5; X-ray; 3.10 A; A=77-233.
DR PDB; 4G3Y; X-ray; 2.60 A; C=77-233.
DR PDB; 4TSV; X-ray; 1.80 A; A=84-233.
DR PDB; 5TSW; X-ray; 2.50 A; A/B/C/D/E/F=84-233.
DR PDBsum; 1A8M; -.
DR PDBsum; 1TNF; -.
DR PDBsum; 2AZ5; -.
DR PDBsum; 2E7A; -.
DR PDBsum; 2TUN; -.
DR PDBsum; 2ZJC; -.
DR PDBsum; 2ZPX; -.
DR PDBsum; 3ALQ; -.
DR PDBsum; 3IT8; -.
DR PDBsum; 3L9J; -.
DR PDBsum; 3WD5; -.
DR PDBsum; 4G3Y; -.
DR PDBsum; 4TSV; -.
DR PDBsum; 5TSW; -.
DR ProteinModelPortal; P01375; -.
DR SMR; P01375; 85-233.
DR DIP; DIP-2895N; -.
DR IntAct; P01375; 30.
DR MINT; MINT-1131842; -.
DR STRING; 9606.ENSP00000392858; -.
DR BindingDB; P01375; -.
DR ChEMBL; CHEMBL1825; -.
DR DrugBank; DB00051; Adalimumab.
DR DrugBank; DB00640; Adenosine.
DR DrugBank; DB01427; Amrinone.
DR DrugBank; DB01076; Atorvastatin.
DR DrugBank; DB00608; Chloroquine.
DR DrugBank; DB01407; Clenbuterol.
DR DrugBank; DB00005; Etanercept.
DR DrugBank; DB01296; Glucosamine.
DR DrugBank; DB00065; Infliximab.
DR DrugBank; DB00704; Naltrexone.
DR DrugBank; DB01411; Pranlukast.
DR DrugBank; DB01366; Procaterol.
DR DrugBank; DB01232; Saquinavir.
DR DrugBank; DB00641; Simvastatin.
DR DrugBank; DB01041; Thalidomide.
DR PhosphoSite; P01375; -.
DR UniCarbKB; P01375; -.
DR DMDM; 135934; -.
DR PaxDb; P01375; -.
DR PRIDE; P01375; -.
DR DNASU; 7124; -.
DR Ensembl; ENST00000376122; ENSP00000365290; ENSG00000204490.
DR Ensembl; ENST00000383496; ENSP00000372988; ENSG00000206439.
DR Ensembl; ENST00000412275; ENSP00000392858; ENSG00000228321.
DR Ensembl; ENST00000420425; ENSP00000410668; ENSG00000228849.
DR Ensembl; ENST00000443707; ENSP00000389492; ENSG00000230108.
DR Ensembl; ENST00000448781; ENSP00000389490; ENSG00000223952.
DR Ensembl; ENST00000449264; ENSP00000398698; ENSG00000232810.
DR GeneID; 7124; -.
DR KEGG; hsa:7124; -.
DR UCSC; uc003nui.4; human.
DR CTD; 7124; -.
DR GeneCards; GC06P031543; -.
DR GeneCards; GC06Pj31530; -.
DR GeneCards; GC06Pk31525; -.
DR GeneCards; GC06Pl31582; -.
DR GeneCards; GC06Pm31619; -.
DR GeneCards; GC06Pn31533; -.
DR GeneCards; GC06Po31533; -.
DR H-InvDB; HIX0165948; -.
DR HGNC; HGNC:11892; TNF.
DR MIM; 191160; gene.
DR MIM; 607507; phenotype.
DR MIM; 610424; phenotype.
DR MIM; 611162; phenotype.
DR neXtProt; NX_P01375; -.
DR Orphanet; 40050; Adult psoriatic arthritis.
DR PharmGKB; PA435; -.
DR eggNOG; NOG40413; -.
DR HOGENOM; HOG000048729; -.
DR HOVERGEN; HBG012516; -.
DR InParanoid; P01375; -.
DR KO; K03156; -.
DR OMA; PWYEPIY; -.
DR OrthoDB; EOG7V4B0Q; -.
DR PhylomeDB; P01375; -.
DR Reactome; REACT_578; Apoptosis.
DR ChiTaRS; TNF; human.
DR EvolutionaryTrace; P01375; -.
DR GeneWiki; Tumor_necrosis_factor-alpha; -.
DR GenomeRNAi; 7124; -.
DR NextBio; 27879; -.
DR PMAP-CutDB; P01375; -.
DR PRO; PR:P01375; -.
DR ArrayExpress; P01375; -.
DR Bgee; P01375; -.
DR CleanEx; HS_TNF; -.
DR Genevestigator; P01375; -.
DR GO; GO:0009897; C:external side of plasma membrane; ISS:BHF-UCL.
DR GO; GO:0005615; C:extracellular space; IDA:BHF-UCL.
DR GO; GO:0005887; C:integral to plasma membrane; IDA:BHF-UCL.
DR GO; GO:0045121; C:membrane raft; IDA:BHF-UCL.
DR GO; GO:0001891; C:phagocytic cup; ISS:BHF-UCL.
DR GO; GO:0055037; C:recycling endosome; ISS:BHF-UCL.
DR GO; GO:0005125; F:cytokine activity; IDA:BHF-UCL.
DR GO; GO:0042802; F:identical protein binding; IDA:BHF-UCL.
DR GO; GO:0044212; F:transcription regulatory region DNA binding; IDA:UniProtKB.
DR GO; GO:0005164; F:tumor necrosis factor receptor binding; IDA:BHF-UCL.
DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; IDA:UniProtKB.
DR GO; GO:0000187; P:activation of MAPK activity; IDA:BHF-UCL.
DR GO; GO:0000185; P:activation of MAPKKK activity; IDA:BHF-UCL.
DR GO; GO:0019722; P:calcium-mediated signaling; IEA:Ensembl.
DR GO; GO:0001775; P:cell activation; IEA:Ensembl.
DR GO; GO:0071230; P:cellular response to amino acid stimulus; IEA:Ensembl.
DR GO; GO:0071316; P:cellular response to nicotine; IDA:UniProtKB.
DR GO; GO:0002439; P:chronic inflammatory response to antigenic stimulus; IMP:BHF-UCL.
DR GO; GO:0050830; P:defense response to Gram-positive bacterium; IEA:Ensembl.
DR GO; GO:0048566; P:embryonic digestive tract development; IEP:DFLAT.
DR GO; GO:0060664; P:epithelial cell proliferation involved in salivary gland morphogenesis; IEA:Ensembl.
DR GO; GO:0030198; P:extracellular matrix organization; IEA:Ensembl.
DR GO; GO:0008625; P:extrinsic apoptotic signaling pathway via death domain receptors; IDA:UniProtKB.
DR GO; GO:0006006; P:glucose metabolic process; IEA:Ensembl.
DR GO; GO:0006959; P:humoral immune response; IEA:Ensembl.
DR GO; GO:0007254; P:JNK cascade; IEA:Ensembl.
DR GO; GO:0050901; P:leukocyte tethering or rolling; IDA:BHF-UCL.
DR GO; GO:0031663; P:lipopolysaccharide-mediated signaling pathway; IDA:UniProtKB.
DR GO; GO:0000165; P:MAPK cascade; IMP:UniProtKB.
DR GO; GO:0097527; P:necroptotic signaling pathway; IDA:UniProtKB.
DR GO; GO:0010693; P:negative regulation of alkaline phosphatase activity; IEA:Ensembl.
DR GO; GO:0061048; P:negative regulation of branching involved in lung morphogenesis; IDA:UniProtKB.
DR GO; GO:0008285; P:negative regulation of cell proliferation; IEA:Ensembl.
DR GO; GO:0002740; P:negative regulation of cytokine secretion involved in immune response; IDA:BHF-UCL.
DR GO; GO:2001240; P:negative regulation of extrinsic apoptotic signaling pathway in absence of ligand; IDA:BHF-UCL.
DR GO; GO:0045599; P:negative regulation of fat cell differentiation; NAS:BHF-UCL.
DR GO; GO:0046325; P:negative regulation of glucose import; IEA:Ensembl.
DR GO; GO:0044130; P:negative regulation of growth of symbiont in host; IEA:Ensembl.
DR GO; GO:0032715; P:negative regulation of interleukin-6 production; IDA:BHF-UCL.
DR GO; GO:0002037; P:negative regulation of L-glutamate transport; IEA:Ensembl.
DR GO; GO:0050995; P:negative regulation of lipid catabolic process; IDA:BHF-UCL.
DR GO; GO:0010888; P:negative regulation of lipid storage; NAS:BHF-UCL.
DR GO; GO:0045668; P:negative regulation of osteoblast differentiation; IEA:Ensembl.
DR GO; GO:0043242; P:negative regulation of protein complex disassembly; IDA:UniProtKB.
DR GO; GO:0000122; P:negative regulation of transcription from RNA polymerase II promoter; IDA:UniProtKB.
DR GO; GO:0045071; P:negative regulation of viral genome replication; IDA:BHF-UCL.
DR GO; GO:0009887; P:organ morphogenesis; IEA:Ensembl.
DR GO; GO:0030316; P:osteoclast differentiation; IEA:Ensembl.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IDA:UniProtKB.
DR GO; GO:0060559; P:positive regulation of calcidiol 1-monooxygenase activity; IDA:BHF-UCL.
DR GO; GO:2000343; P:positive regulation of chemokine (C-X-C motif) ligand 2 production; IDA:BHF-UCL.
DR GO; GO:0045080; P:positive regulation of chemokine biosynthetic process; IDA:BHF-UCL.
DR GO; GO:0002876; P:positive regulation of chronic inflammatory response to antigenic stimulus; IEA:Ensembl.
DR GO; GO:0050715; P:positive regulation of cytokine secretion; IDA:BHF-UCL.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; NAS:BHF-UCL.
DR GO; GO:0031622; P:positive regulation of fever generation; ISS:BHF-UCL.
DR GO; GO:0051798; P:positive regulation of hair follicle development; IEA:Ensembl.
DR GO; GO:0034116; P:positive regulation of heterotypic cell-cell adhesion; IDA:BHF-UCL.
DR GO; GO:0002925; P:positive regulation of humoral immune response mediated by circulating immunoglobulin; IEA:Ensembl.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB cascade; IDA:BHF-UCL.
DR GO; GO:0032729; P:positive regulation of interferon-gamma production; IEA:Ensembl.
DR GO; GO:0032755; P:positive regulation of interleukin-6 production; IEA:Ensembl.
DR GO; GO:0045416; P:positive regulation of interleukin-8 biosynthetic process; IDA:BHF-UCL.
DR GO; GO:0046330; P:positive regulation of JNK cascade; IEA:Ensembl.
DR GO; GO:0043507; P:positive regulation of JUN kinase activity; IDA:UniProtKB.
DR GO; GO:0051044; P:positive regulation of membrane protein ectodomain proteolysis; IDA:BHF-UCL.
DR GO; GO:0045840; P:positive regulation of mitosis; IEA:Ensembl.
DR GO; GO:0071677; P:positive regulation of mononuclear cell migration; NAS:BHF-UCL.
DR GO; GO:0010940; P:positive regulation of necrotic cell death; TAS:BHF-UCL.
DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0042346; P:positive regulation of NF-kappaB import into nucleus; IDA:BHF-UCL.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IDA:UniProtKB.
DR GO; GO:0051533; P:positive regulation of NFAT protein import into nucleus; IDA:MGI.
DR GO; GO:0045429; P:positive regulation of nitric oxide biosynthetic process; IDA:BHF-UCL.
DR GO; GO:0045672; P:positive regulation of osteoclast differentiation; IDA:BHF-UCL.
DR GO; GO:0033138; P:positive regulation of peptidyl-serine phosphorylation; IDA:BHF-UCL.
DR GO; GO:0071803; P:positive regulation of podosome assembly; IDA:BHF-UCL.
DR GO; GO:0043243; P:positive regulation of protein complex disassembly; IDA:UniProtKB.
DR GO; GO:0051897; P:positive regulation of protein kinase B signaling cascade; IEA:Ensembl.
DR GO; GO:2000010; P:positive regulation of protein localization to cell surface; IDA:BHF-UCL.
DR GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; IDA:BHF-UCL.
DR GO; GO:0050806; P:positive regulation of synaptic transmission; IEA:Ensembl.
DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IDA:UniProtKB.
DR GO; GO:0045994; P:positive regulation of translational initiation by iron; IEA:Ensembl.
DR GO; GO:0060557; P:positive regulation of vitamin D biosynthetic process; IDA:BHF-UCL.
DR GO; GO:0000060; P:protein import into nucleus, translocation; IDA:UniProtKB.
DR GO; GO:0043491; P:protein kinase B signaling cascade; IMP:UniProtKB.
DR GO; GO:0032800; P:receptor biosynthetic process; IDA:BHF-UCL.
DR GO; GO:0060693; P:regulation of branching involved in salivary gland morphogenesis; IEA:Ensembl.
DR GO; GO:0051023; P:regulation of immunoglobulin secretion; IEA:Ensembl.
DR GO; GO:0050796; P:regulation of insulin secretion; IDA:BHF-UCL.
DR GO; GO:0014823; P:response to activity; IEA:Ensembl.
DR GO; GO:0042493; P:response to drug; IEA:Ensembl.
DR GO; GO:0051384; P:response to glucocorticoid stimulus; IDA:BHF-UCL.
DR GO; GO:0001666; P:response to hypoxia; IEA:Ensembl.
DR GO; GO:0009612; P:response to mechanical stimulus; IEA:Ensembl.
DR GO; GO:0009651; P:response to salt stress; TAS:BHF-UCL.
DR GO; GO:0009615; P:response to virus; IDA:BHF-UCL.
DR GO; GO:0030730; P:sequestering of triglyceride; IDA:BHF-UCL.
DR GO; GO:0003009; P:skeletal muscle contraction; IEA:Ensembl.
DR GO; GO:0006927; P:transformed cell apoptotic process; IDA:BHF-UCL.
DR GO; GO:0033209; P:tumor necrosis factor-mediated signaling pathway; IMP:BHF-UCL.
DR Gene3D; 2.60.120.40; -; 1.
DR InterPro; IPR006053; TNF.
DR InterPro; IPR002959; TNF_alpha.
DR InterPro; IPR021184; TNF_CS.
DR InterPro; IPR006052; TNF_dom.
DR InterPro; IPR008064; TNFalpha/TNFSF15.
DR InterPro; IPR008983; Tumour_necrosis_fac-like_dom.
DR PANTHER; PTHR11471:SF7; PTHR11471:SF7; 1.
DR Pfam; PF00229; TNF; 1.
DR PRINTS; PR01234; TNECROSISFCT.
DR PRINTS; PR01235; TNFALPHA.
DR SMART; SM00207; TNF; 1.
DR SUPFAM; SSF49842; SSF49842; 1.
DR PROSITE; PS00251; TNF_1; 1.
DR PROSITE; PS50049; TNF_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cell membrane; Complete proteome; Cytokine;
KW Direct protein sequencing; Disulfide bond; Glycoprotein; Lipoprotein;
KW Membrane; Myristate; Phosphoprotein; Polymorphism; Reference proteome;
KW Secreted; Signal-anchor; Transmembrane; Transmembrane helix.
FT CHAIN 1 233 Tumor necrosis factor, membrane form.
FT /FTId=PRO_0000034423.
FT CHAIN 1 39 Intracellular domain 1.
FT /FTId=PRO_0000417231.
FT CHAIN 1 35 Intracellular domain 2.
FT /FTId=PRO_0000417232.
FT CHAIN 50 ? C-domain 1.
FT /FTId=PRO_0000417233.
FT CHAIN 52 ? C-domain 2.
FT /FTId=PRO_0000417234.
FT CHAIN 77 233 Tumor necrosis factor, soluble form.
FT /FTId=PRO_0000034424.
FT TOPO_DOM 1 35 Cytoplasmic (Potential).
FT TRANSMEM 36 56 Helical; Signal-anchor for type II
FT membrane protein; (Potential).
FT TOPO_DOM 57 233 Extracellular (Potential).
FT SITE 35 36 Cleavage; by SPPL2A or SPPL2B.
FT SITE 39 40 Cleavage; by SPPL2A or SPPL2B.
FT SITE 49 50 Cleavage; by SPPL2A or SPPL2B.
FT SITE 51 52 Cleavage; by SPPL2A or SPPL2B.
FT SITE 76 77 Cleavage; by ADAM17.
FT MOD_RES 2 2 Phosphoserine; by CK1 (Probable).
FT LIPID 19 19 N6-myristoyl lysine.
FT LIPID 20 20 N6-myristoyl lysine.
FT CARBOHYD 80 80 O-linked (GalNAc...); in soluble form.
FT DISULFID 145 177
FT VARIANT 84 84 P -> L (in dbSNP:rs4645843).
FT /FTId=VAR_019378.
FT VARIANT 94 94 A -> T (in dbSNP:rs1800620).
FT /FTId=VAR_011927.
FT MUTAGEN 105 105 L->S: Low activity.
FT MUTAGEN 108 108 R->W: Biologically inactive.
FT MUTAGEN 112 112 L->F: Biologically inactive.
FT MUTAGEN 160 160 A->V: Biologically inactive.
FT MUTAGEN 162 162 S->F: Biologically inactive.
FT MUTAGEN 167 167 V->A,D: Biologically inactive.
FT MUTAGEN 222 222 E->K: Biologically inactive.
FT CONFLICT 63 63 F -> S (in Ref. 5; AAA61198).
FT CONFLICT 84 86 PSD -> VNR (in Ref. 17; AAF71992).
FT CONFLICT 183 183 E -> R (in Ref. 16; AAC03542).
FT STRAND 89 94
FT STRAND 96 98
FT STRAND 99 101
FT STRAND 106 108
FT STRAND 112 114
FT STRAND 118 120
FT STRAND 123 125
FT STRAND 130 144
FT STRAND 146 148
FT STRAND 152 159
FT HELIX 161 163
FT STRAND 167 174
FT STRAND 177 179
FT STRAND 182 185
FT STRAND 189 202
FT STRAND 207 213
FT HELIX 215 217
FT STRAND 221 223
FT STRAND 225 232
SQ SEQUENCE 233 AA; 25644 MW; 3DF90F96C9031FFE CRC64;
MSTESMIRDV ELAEEALPKK TGGPQGSRRC LFLSLFSFLI VAGATTLFCL LHFGVIGPQR
EEFPRDLSLI SPLAQAVRSS SRTPSDKPVA HVVANPQAEG QLQWLNRRAN ALLANGVELR
DNQLVVPSEG LYLIYSQVLF KGQGCPSTHV LLTHTISRIA VSYQTKVNLL SAIKSPCQRE
TPEGAEAKPW YEPIYLGGVF QLEKGDRLSA EINRPDYLDF AESGQVYFGI IAL
//

MIM 191160
*RECORD*
*FIELD* NO
191160
*FIELD* TI
*191160 TUMOR NECROSIS FACTOR; TNF
;;TUMOR NECROSIS FACTOR, ALPHA; TNFA;;
CACHECTIN;;
read moreTNF, MONOCYTE-DERIVED;;
TNF, MACROPHAGE-DERIVED
*FIELD* TX

DESCRIPTION

Tumor necrosis factor (TNF) is a multifunctional proinflammatory
cytokine secreted predominantly by monocytes/macrophages that has
effects on lipid metabolism, coagulation, insulin resistance, and
endothelial function. TNF was originally identified in mouse serum after
injection with Mycobacterium bovis strain bacillus Calmette-Guerin (BCG)
and endotoxin. Serum from such animals was cytotoxic or cytostatic to a
number of mouse and human transformed cell lines and produced
hemorrhagic necrosis and in some instances complete regression of
certain transplanted tumors in mice (Shirai et al., 1985; Pennica et
al., 1984).

CLONING

Pennica et al. (1984) identified a monocyte-like human cell line that
provided a source of TNF and its messenger RNA. cDNA clones were
isolated, sequenced, and translated in E. coli. TNF and LTA (153440), or
TNFB, have similar biologic activities and share 30% amino acid
homology.

Wang et al. (1985) and Shirai et al. (1985) independently cloned cDNA
sequences corresponding to the human TNF gene. The deduced 233-amino
acid protein has a long leader sequence of 76 residues. The gene was
expressed in E. coli, and the protein product produced necrosis of
murine tumors in vivo.

TNF is synthesized as a 26-kD membrane-bound protein (pro-TNF) that is
cleaved by processing enzymes (see, e.g., ADAM17; 603639 and Black et
al., 1997) to release a soluble 17-kD TNF molecule The soluble molecule
can then bind to its main receptors TNFR1 (191190) and TNFR2 (191191)
(Skoog et al., 1999).

GENE FUNCTION

Aggarwal et al. (1985) presented evidence that TNF-alpha and TNF-beta
share a common receptor on tumor cells and that the receptors are
upregulated by gamma-interferon. Various interferons have been known to
be synergistic with TNF in antitumor effects in vitro. Brenner et al.
(1989) demonstrated that TNFA stimulates prolonged activation of the
oncogene JUN expression; the JUN gene (165160) encodes transcription
factor AP-1, which stimulates collagenase gene transcription. Thus,
activation of JUN and collagenase gene expression may be one mechanism
for mediating some of the biologic effects of TNFA.

Obeid et al. (1993) found that the intracellular concentration of
ceramide increased by 45% at 10 minutes after the addition of TNF-alpha
to cells in vivo. Treatment of cells with ceramide directly induced DNA
fragmentation, an early marker of apoptosis. The authors concluded that
TNF-alpha resulted in sphingomyelin hydrolysis, production of ceramide,
and ceramide-mediated apoptosis.

Franchimont et al. (1999) examined the ability of TNFA and IL10 (124092)
to regulate differentially the sensitivity of human
monocytes/macrophages to glucocorticoids. Dexamethasone had different
effects on LPS-induced TNFA and IL10 secretion; whereas it suppressed
TNFA in a dose-dependent fashion, its effect on IL10 secretion was
biphasic, producing stimulation at lower doses and inhibition at higher
doses. The concentration of LPS employed influenced the effect of
dexamethasone on IL10 secretion (P less than 0.001). Pretreatment with
TNFA diminished, and with IL10 improved, the ability of dexamethasone to
suppress IL6 (147620) secretion in whole-blood cell cultures (P less
than 0.01 for both) and to enhance IL1 receptor antagonist (IL1RN;
147679) secretion by U937 cells (P less than 0.05 for both). TNFA
decreased (P less than 0.001), while IL10 increased (P less than 0.001),
the concentration of dexamethasone binding sites in these cells, with no
discernible effect on their binding affinity. The authors concluded that
glucocorticoids differentially modulate TNFA and IL10 secretion by human
monocytes in an LPS dose-dependent fashion, and that the sensitivity of
these cells to glucocorticoids is altered by TNFA or IL10 pretreatment;
TNFA blocks their effects, whereas IL10 acts synergistically with
glucocorticoids.

Garcia-Ruiz et al. (2003) studied the contribution of ASM in
TNF-alpha-mediated hepatocellular apoptosis. They showed that selective
mGSH (mitochondrial glutathione) depletion sensitized hepatocytes to
TNF-alpha-mediated hepatocellular apoptosis by facilitating the onset of
mitochondrial permeability transition. Inactivation of endogenous
hepatocellular ASM activity protected hepatocytes from TNF-alpha-induced
cell death. Similarly, ASM -/- mice were resistant in vivo to endogenous
and exogenous TNF-alpha-induced liver damage. Targeting of ganglioside
GD3 (601123) to mitochondria occurred in ASM +/+ but not in ASM -/-
hepatocytes. Treatment of ASM -/- hepatocytes with exogenous ASM induced
the colocalization of GD3 and mitochondria. Garcia-Ruiz et al. (2003)
concluded that ASM contributes to TNF-alpha-induced hepatocellular
apoptosis by promoting the targeting of mitochondria by
glycosphingolipids.

Beattie et al. (2002) demonstrated that TNF-alpha, produced by glia,
enhances synaptic efficacy by increasing surface expression of AMPA
receptors. Preventing the actions of endogenous TNF-alpha has the
opposite effects. Thus, Beattie et al. (2002) concluded that the
continual presence of TNF-alpha is required for preservation of synaptic
strength at excitatory synapses. Through its effects on AMPA receptor
trafficking, TNF-alpha may play roles in synaptic plasticity and
modulating responses to neural injury.

Ruuls and Sedgwick (1999) reviewed the problem of unlinking TNF biology
from that of the MHC. Dysregulation and, in particular, overproduction
of TNF have been implicated in a variety of human diseases, including
sepsis, cerebral malaria (611162), and autoimmune diseases such as
multiple sclerosis (MS; 126200), rheumatoid arthritis, systemic lupus
erythematosus (152700), and Crohn disease (see 266600), as well as
cancer. Susceptibility to many of these diseases is thought to have a
genetic basis, and the TNF gene is considered a candidate predisposing
gene. However, unraveling the importance of genetic variation in the TNF
gene to disease susceptibility or severity is complicated by its
location within the MHC, a highly polymorphic region that encodes
numerous genes involved in immunologic responses. Ruuls and Sedgwick
(1999) reviewed studies that had analyzed the contribution of TNF and
related genes to susceptibility to human disease, and they discussed how
the presence of the TNF gene within the MHC may potentially complicate
the interpretation of studies in animal models in which the TNF gene is
experimentally manipulated.

Progressive oligodendrocyte loss is part of the pathogenesis of MS.
Oligodendrocytes are vulnerable to a variety of mediators of cell death,
including free radicals, proteases, inflammatory cytokines, and
glutamate excitotoxicity. Proinflammatory cytokine release in MS is
mediated in part by microglial activation. Takahashi et al. (2003) found
that interleukin-1-beta (IL1B; 147720) and TNF-alpha, prominent
microglia-derived cytokines, caused oligodendrocyte death in coculture
with astrocytes and microglia, but not in pure culture of
oligodendrocytes alone. Because IL1B had been shown to impair the
activity of astrocytes in the uptake and metabolism of glutamate,
Takahashi et al. (2003) hypothesized that the indirect toxic effect of
microglia-derived IL1B and TNFA on oligodendrocytes involved increased
glutamate excitotoxicity via modulation of astrocyte activity. In
support, antagonists at glutamate receptors blocked the toxicity. The
findings provided a mechanistic link between microglial activation in MS
with glutamate-induced oligodendrocyte destruction.

Steed et al. (2003) used structure-based design to engineer variant TNF
proteins that rapidly form heterotrimers with native TNF to give
complexes that neither bind to nor stimulate signaling through TNF
receptors. Thus, TNF is inactivated by sequestration. Dominant-negative
TNFs were thought to represent a possible approach to antiinflammatory
biotherapeutics, and experiments in animal models showed that the
strategy can attenuate TNF-mediated pathology.

Using an integrated approach comprising tandem affinity purification,
liquid chromatography tandem mass spectrometry, network analysis, and
directed functional perturbation studies using RNA interference or
loss-of-function analysis, Bouwmeester et al. (2004) identified 221
molecular associations and 80 previously unknown interactors, including
10 novel functional modulators, of the TNFA/NFKB signal transduction
pathway.

Kamata et al. (2005) found that TNF-alpha-induced reactive oxygen
species (ROS), whose accumulation could be suppressed by mitochondrial
superoxide dismutase (SOD2; 147460), caused oxidation and inhibition of
JNK (see 601158)-inactivating phosphatases by converting their catalytic
cysteine to sulfenic acid. This resulted in sustained JNK activation,
which is required for cytochrome c (see 123995) release and caspase-3
(CASP3; 600636) cleavage, as well as necrotic cell death. Treatment of
cells or experimental animals with an antioxidant prevented H2O2
accumulation, JNK phosphatase oxidation, sustained JNK activity, and
both forms of cell death. Antioxidant treatment also prevented
TNF-alpha-mediated fulminant liver failure without affecting liver
regeneration.

Membrane traffic in activated macrophages is required for 2 critical
events in innate immunity: proinflammatory cytokine secretion and
phagocytosis of pathogens. Murray et al. (2005) found a joint
trafficking pathway linking both actions, which may economize membrane
transport and augment the immune response. TNFA is trafficked from the
Golgi to the recycling endosome, where vesicle-associated membrane
protein-3 (VAMP3; 603657) mediates its delivery to the cell surface at
the site of phagocytic cup formation. Fusion of the recycling endosome
at the cup simultaneously allows rapid release of TNF-alpha and expands
the membrane for phagocytosis.

Using live-cell imaging, Lieu et al. (2008) showed that tubules and
carriers expressing p230 (GOLGA4; 602509) selectively mediated TNF
transport from the trans-Golgi network (TGN) in HeLa cells. LPS
activation of macrophages caused a dramatic increase in p230-labeled
tubules and carriers emerging from the TGN. Depletion of p230 in
macrophages reduced cell surface delivery of TNF more than 10-fold
compared with control cells. Mice with RNA interference-mediated
silencing of p230 also had dramatically reduced surface expression of
Tnf. Lieu et al. (2008) concluded that p230 is a key regulator of TNF
secretion and that LPS activation of macrophages increases Golgi
carriers for export.

Stellwagen and Malenka (2006) showed that synaptic scaling in response
to prolonged blockade of activity is mediated by the proinflammatory
cytokine TNF-alpha. Using mixtures of wildtype and TNF-alpha-deficient
neurons and glia, they showed that glia are the source of the TNF-alpha
that is required for this form of synaptic scaling. Stellwagen and
Malenka (2006) suggested that by modulating TNF-alpha levels, glia
actively participate in the homeostatic activity-dependent regulation of
synaptic connectivity.

Kawane et al. (2006) showed that DNase II (see 126350)-null/interferon
type I receptor (IFNIR)-null mice and mice with an induced deletion of
the DNase II gene developed a chronic polyarthritis resembling human
rheumatoid arthritis. A set of cytokine genes was strongly activated in
the affected joints of these mice, and their serum contained high levels
of anticyclic citrullinated peptide antibody, rheumatoid factor, and
matrix metalloproteinase-3 (see 185250). Early in the pathogenesis,
expression of the TNFA gene was upregulated in the bone marrow, and
administration of anti-TNFA antibody prevented the development of
arthritis. Kawane et al. (2006) concluded that if macrophages cannot
degrade mammalian DNA from erythroid precursors and apoptotic cells,
they produce TNFA, which activates synovial cells to produce various
cytokines, leading to the development of chronic polyarthritis.

Tay et al. (2010) used high-throughput microfluidic cell culture and
fluorescence microscopy, quantitative gene expression analysis, and
mathematical modeling to investigate how single mammalian cells respond
to different concentrations of TNF-alpha and relay information to the
gene expression programs by means of the transcription factor NF-kappa-B
(see 164011). Tay et al. (2010) measured NF-kappa-B activity in
thousands of live cells under TNF-alpha doses covering 4 orders of
magnitude. They found that, in contrast to population-level studies with
bulk assays, the activation was heterogeneous and was a digital process
at the single-cell level with fewer cells responding at lower doses.
Cells also encoded a subtle set of analog parameters, including
NF-kappa-B peak intensity, response time, and number of oscillations, to
modulate the outcome. Tay et al. (2010) developed a stochastic
mathematical model that reproduced both the digital and analog dynamics,
as well as most gene expression profiles, at all measured conditions,
constituting a broadly applicable model for TNA-alpha-induced NF-kappa-B
signaling in various types of cells.

Francisella tularensis, the causative agent of tularemia and a potential
biohazard threat, evades the immune response, including innate responses
through the lipopolysaccharide receptor TLR4 (603030), thus increasing
its virulence. Huang et al. (2010) deleted the bacterium's ripA gene and
found that mouse macrophages and a human monocyte line produced
significant amounts of the inflammatory cytokines TNF, IL18 (600953),
and IL1B in response to the mutant. IL1B and IL18 secretion was
dependent on PYCARD (606838) and CASP1 (147678), and MYD88 (602170) was
required for inflammatory cytokine synthesis. A complemented strain with
restored expression of ripA restored immune evasion, as well as
activation of the MAP kinases ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948),
JNK, and p38 (MAPK14; 600289). Pharmacologic inhibition of these MAPKs
reduced cytokine induction by the ripA deletion mutant. Mice infected
with the mutant exhibited stronger Il1b and Tnfa responses than mice
infected with the wildtype live vaccine strain. Huang et al. (2010)
concluded that the F. tularensis ripA gene product functions by
suppressing MAPK pathways and circumventing the inflammasome response.

Gunther et al. (2011) demonstrated a critical role for caspase-8 (CASP8;
601763) in regulating necroptosis of intestinal epithelial cells (IECs)
and terminal ileitis. Mice with a conditional deletion of caspase-8 in
the intestinal epithelium (Casp8-delta-IEC) spontaneously developed
inflammatory lesions in the terminal ileum were highly susceptible to
colitis. These mice lacked Paneth cells and showed reduced numbers of
goblet cells, indicating dysregulated antimicrobial immune cell
functions of the intestinal epithelium. Casp8-delta-IEC mice showed
increased cell death in the Paneth cell area of small intestinal crypts.
Epithelial cell death was induced by TNF-alpha, was associated with
increased expression of receptor-interacting protein-3 (RIP3; 605817),
and could be inhibited on blockade of necroptosis. Lastly, Gunther et
al. (2011) identified high levels of RIP3 in human Paneth cells and
increased necroptosis in the terminal ileum of patients with Crohn
disease, suggesting a potential role of necroptosis in the pathogenesis
of this disease. Gunther et al. (2011) concluded that their data
demonstrated a critical function of caspase-8 in regulating intestinal
homeostasis and in protecting IECs from TNF-alpha-induced necroptotic
cell death.

Braumuller et al. (2013) showed that the combined action of the T
helper-1-cell cytokines IFN-gamma (IFNG; 147570) and TNF directly
induces permanent growth arrest in cancers. To safely separate
senescence induced by tumor immunity from oncogene-induced senescence,
Braumuller et al. (2013) used a mouse model in which the Simian virus-40
large T antigen (Tag) expressed under the control of the rat insulin
promoter creates tumors by attenuating p53 (191170)- and Rb
(614041)-mediated cell cycle control. When combined, Ifng and Tnf drive
Tag-expressing cancers into senescence by inducing permanent growth
arrest in G1/G0, activation of p16Ink4a (CDKN2A; 600160), and downstream
Rb hypophosphorylation at ser795. This cytokine-induced senescence
strictly requires Stat1 (600555) and Tnfr1 (TNFRSF1A; 191190) signaling
in addition to p16Ink4a. In vivo, Tag-specific T-helper-1 cells
permanently arrest Tag-expressing cancers by inducing Ifng- and
Tnfr1-dependent senescence. Conversely, Tnfr1-null Tag-expressing
cancers resist cytokine-induced senescence and grow aggressively, even
in Tnfr1-expressing hosts. Braumuller et al. (2013) concluded that as
IFNG and TNF induce senescence in numerous murine and human cancers,
this may be a general mechanism for arresting cancer progression.

Li et al. (2014) found that knockdown of the long noncoding RNA THRIL
(615622) in human THP1 macrophages strongly suppressed TNF induction.
Expression of TNF resulted in decreased expression of THRIL. Pull-down
analysis identified a specific interaction of THRIL, primarily its
5-prime end, with HNRNPL (603083). Knockdown of HNRNPL resulted in
decreased TNF production by stimulated THP1 cells. Chromatin
immunoprecipitation analysis revealed binding of HNRNPL to the TNF
promoter, and chromatin isolation by RNA purification assays showed that
THRIL was also present at the TNF promoter. Knockdown of THRIL reduced
binding of HNRNPL to the TNF promoter. Li et al. (2014) concluded that
HNRNPL and THRIL form a ribonucleoprotein complex that stimulates TNF
transcription by binding to its promoter. By examining RNA samples from
patients with Kawasaki disease (611775), Li et al. (2014) observed that
THRIL expression was significantly lower in the acute phase, when serum
TNF levels are elevated, compared with the convalescent phase. They
proposed that the low levels of THRIL when TNF levels are high in
Kawasaki disease mirrors the negative-feedback loop of THRIL regulation
observed in in vitro experiments and suggested that THRIL may be a
biomarker for immune activation.

- Role in Psoriasis

Inflammatory cytokines such as TNF have been implicated in the
pathogenesis of psoriasis (see 177900) (Bonifati and Ameglio, 1999).
Leonardi et al. (2003) found that treatment with the TNF antagonist
etanercept led to a significant reduction in the severity of psoriasis
over a treatment period of 24 weeks.

Boyman et al. (2004) engrafted keratome biopsies of human symptomless
prepsoriatic skin onto AGR129 mice, which are deficient in type I and
type II interferon receptors (see 107450 and 107470, respectively), as
well as Rag2 (179616), and thereby lack B and T cells and show severely
impaired NK cell activity. Upon engraftment, human T cells underwent
local proliferation, which was crucial for development of a psoriatic
phenotype exhibiting papillomatosis and acanthosis. Immunohistochemical
analysis of prepsoriatic skin before transplantation and 8 weeks after
transplantation showed activation of epidermal keratinocytes, dendritic
cells, endothelial cells, and immune cells in the transplanted tissue.
T-cell proliferation and the subsequent disease development were
dependent on TNF production and could be inhibited by antibody or
soluble receptor to TNF. Boyman et al. (2004) concluded that
TNF-dependent activation of resident T cells is necessary and sufficient
for development of psoriatic lesions.

- Role in Rheumatoid Arthritis and Ankylosing Spondylitis

TNF-alpha may play a part in the pathogenesis of ankylosing spondylitis
(106300) and rheumatoid arthritis (RA; 180300). Gorman et al. (2002)
tested the efficacy of inhibition of TNF-alpha in treatment of
ankylosing spondylitis. They used etanercept, a dimeric fusion protein
of the human 75-kD (p75) TNFR2 (TNFRSF1B; 191191) linked to the Fc
portion of human IgG1 (147100). Treatment in 40 patients with active,
inflammatory disease for 4 months resulted in rapid, significant, and
sustained improvement.

Nadkarni et al. (2007) had previously shown that anti-TNF (infliximab)
therapy could overcome the inability of CD4 (186940)-positive/CD25
(IL2RA; 147730)-high regulatory T (Treg) cells from RA patients to
suppress proinflammatory cytokine production by
CD4-positive/CD25-negative T cells. Using flow cytometric analysis, they
demonstrated that infliximab therapy induced a
CD4-positive/CD25-high/FOXP3 (300292)-positive Treg population that
mediated suppression via TGFB and IL10 and lacked expression of CD62L
(SELL; 153240), a marker for CD4-positive/CD25-high/FOXP3-positive
'natural' Tregs. Natural Tregs remained defective in RA patients even
after infliximab treatment. Nadkarni et al. (2007) concluded that
anti-TNF therapy in RA patients induces a newly differentiated
population of Tregs capable of restoring tolerance and compensating for
defective natural Tregs.

- Role in Tuberculosis

Studies in mice (Flynn et al., 1995) and observations in patients
receiving infliximab (remicade) for treatment of rheumatoid arthritis
(180300) or Crohn disease (see IBD3; 604519) (Keane et al., 2001) have
shown that antibody-mediated neutralization of TNF increases
susceptibility to tuberculosis (TB; 607948). However, excess TNF may be
associated with severe TB pathology (Barnes et al., 1990). Using path
and segregation analysis and controlling for environmental differences,
Stein et al. (2005) evaluated TNF secretion levels in Ugandan TB
patients. The results suggested that there is a strong genetic
influence, due to a major gene, on TNF expression in TB, and that there
may be heterozygote advantage. The effect of shared environment on TNF
expression in TB was minimal. Stein et al. (2005) concluded that TNF is
an endophenotype for TB that may increase power to detect
disease-predisposing loci.

- Role in Autosomal Dominant Polycystic Kidney Disease

Li et al. (2008) showed that TNF-alpha, which is found in cystic fluid
of humans with autosomal dominant polycystic kidney disease (ADPKD; see
173900), disrupted the localization of polycystin-2 (PKD2; 173910) to
the plasma membrane and primary cilia through TNF-alpha-induced scaffold
protein FIP2 (OPTN; 602432). Treatment of mouse embryonic kidney organ
cultures with TNF-alpha resulted in cyst formation, and this effect was
exacerbated in Pkd2 +/- kidneys. TNF-alpha also stimulated cyst
formation in vivo in Pkd2 +/- mice, and treatment of Pkd2 +/- mice with
a TNF-alpha inhibitor prevented cyst formation.

MOLECULAR GENETICS

Single-nucleotide polymorphisms (SNPs) in regulatory regions of cytokine
genes have been associated with susceptibility to a number of complex
disorders. TNF is a proinflammatory cytokine that provides a rapid form
of host defense against infection but is fatal in excess. Because TNF is
employed against a variety of pathogens, each involving a different
pattern of risks and benefits, it might be expected that this would
favor diversity in the genetic elements that control TNF production.

Herrmann et al. (1998) used PCR-SSCP and sequencing to screen the entire
coding region and 1,053 bp upstream of the transcription start site of
the TNFA gene for polymorphisms. Five polymorphisms were identified: 4
were located in the upstream region at positions -857, -851, -308
(191160.0004), and -238 from the first transcribed nucleotide, and 1 was
found in a nontranslated region at position +691.

Three SNPs located at nucleotides -238, -308, and -376 (191160.0003)
with respect to the TNF transcriptional start site are all substitutions
of adenine for guanine. Knight et al. (1999) referred to the allelic
types as -238G/-238A, -308G/-308A, and -376G/-376A. They stated that
variation in the TNFA promoter region had been found to be associated
with susceptibility to cerebral malaria (McGuire et al., 1994), with
mucocutaneous leishmaniasis (Cabrera et al., 1995), with death from
meningococcal disease (Nadel et al., 1996), with lepromatous leprosy
(Roy et al., 1997), with scarring trachoma (Conway et al., 1997), and
with asthma (Moffatt and Cookson, 1997).

Flori et al. (2003) tested for linkage between polymorphisms within the
MHC region and mild malaria; see 609148. Two-point analysis indicated
linkage of mild malaria to TNFd (lod = 3.27), a highly polymorphic
marker in the MHC region. Multipoint analysis also indicated evidence
for linkage of mild malaria to the MHC region, with a peak close to TNF
(lod = 3.86). The authors proposed that genetic variation within TNF may
influence susceptibility to mild malaria, but the polymorphisms TNF-238,
TNF-244, and TNF-308 (191160.0004) are unlikely to explain linkage of
mild malaria to the MHC region.

Statistical analyses by Funayama et al. (2004) showed a possible
interaction between polymorphisms in the optineurin (OPTN; 602432) and
TNF genes that would increase the risk for the development and probably
progression of glaucoma in Japanese patients with POAG (137760).

By sequencing the promoter regions 500 bp upstream from the
transcriptional start sites of members of the TNF and TNFR
superfamilies, Kim et al. (2005) identified 23 novel regulatory SNPs in
Korean donors. Sequence analysis suggested that 9 of the SNPs altered
putative transcription factor binding sites. Analysis of SNP databases
suggested that the SNP allele frequencies were similar to those for
Japanese subjects but distinct from those of Caucasian or African
populations.

- Insulin Resistance and Diabetes

Zinman et al. (1999) studied the relationship between TNF-alpha and
anthropometric and physiologic variables associated with insulin
resistance and diabetes in an isolated Native Canadian population with
very high rates of NIDDM (125853). Using the homeostasis assessment
(HOMA) model to estimate insulin resistance, they found moderate, but
statistically significant, correlations between TNF-alpha and fasting
insulin, HOMA insulin resistance, waist circumference, fasting
triglycerides, and systolic blood pressure; in all cases, coefficients
for females were stronger than those for males. The authors concluded
that in this homogeneous Native Canadian population, circulating
TNF-alpha concentrations were positively correlated with insulin
resistance across a spectrum of glucose tolerance. The data suggested a
possible role for TNF-alpha in the pathophysiology of insulin
resistance.

Rasmussen et al. (2000) investigated whether the -308 and -238 G-to-A
genetic variants of TNF were associated with features of the insulin
resistance syndrome or alterations in birth weight in 2 Danish study
populations comprising 380 unrelated young healthy subjects and 249
glucose-tolerant relatives of type 2 diabetic patients, respectively.
Neither of the variants was related to altered insulin sensitivity index
or other features of the insulin resistance syndrome. Birth weight and
the ponderal index were also not associated with the polymorphisms.
Their study did not support a major role of the -308 or -238
substitutions in TNF in the pathogenesis of insulin resistance or
altered birth weight among Danish Caucasian subjects.

Obayashi et al. (2000) investigated the influence of TNF-alpha on the
predisposition to insulin dependency in adult-onset diabetic patients
with type I diabetes (IDDM; 222100)-protective HLA haplotypes. Also see
HLA-DQB1 (604305). The TNF-alpha of 3 groups of
DRB1*1502-DQB1*0601-positive diabetic patients who had initially been
nonketotic and noninsulin dependent for more than 1 year was analyzed.
Group A included 11 antibodies to glutamic acid decarboxylase
(GADab)-positive patients who developed insulin dependency within 4
years of diabetes onset. Group B included 11 GADab-positive patients who
remained noninsulin dependent for more than 12 years. Group C included
12 GADab-negative type 2 diabetes, and a control group included 18
nondiabetic subjects. In the group C and control subjects,
DRB1*1502-DQB1*0601 was strongly associated with the TNFA-13 allele.
DRB1*1502-DQB1*0601 was strongly associated with the TNFA-12 allele
among the group A patients, but not among the group B patients.
Interestingly, sera from all patients with non-TNFA-12 and non-TNFA-13
in group B reacted with GAD65 protein by Western blot. The authors
concluded that TNF-alpha is associated with a predisposition to
progression to insulin dependency in GADab/DRB1*1502-DQB1*0601-positive
diabetic patients initially diagnosed with type II diabetes and that
determination of these patients' TNF-alpha genotype may allow for better
prediction of their clinical course.

To study whether the TNFA gene could be a modifying gene for diabetes,
Li et al. (2003) studied TNFA promoter polymorphisms (G-to-A
substitution at positions -308 and -238) in relation to HLA-DQB1
genotypes in type 2 diabetes patients from families with both type 1 and
type 2 diabetes (type 1/2 families) or common type 2 diabetes families
as well as in patients with adult-onset type 1 diabetes and control
subjects. The TNFA(308) AA/AG genotype frequency was increased in
adult-onset type 1 patients (55%, 69 of 126), but it was similar in type
2 patients from type 1/2 families (35%, 33/93) or common type 2 families
(31%, 122 of 395), compared with controls (33%, 95/284; P less than
0.0001 vs type 1). The TNFA(308) A and DQB1*02 alleles were in linkage
disequilibrium in type 1 patients (Ds = 0.81; P less than 0.001 vs Ds =
0.25 in controls) and type 2 patients from type 1/2 families (Ds = 0.59,
P less than 0.05 vs controls) but not in common type 2 patients (Ds =
0.39). The polymorphism was associated with an insulin-deficient
phenotype in type 2 patients from type 1/2 families only together with
DQB*02, whereas the common type 2 patients with AA/AG had lower
waist-to-hip ratio [0.92 (0.12) vs 0.94 (0.11), P = 0.008] and lower
fasting C-peptide concentration [0.48 (0.47) vs 0.62 (0.46) nmol/liter,
P = 0.020] than those with GG, independently of the presence of DQB1*02.
The authors concluded that TNFA is unlikely to be the second gene on the
short arm of chromosome 6 responsible for modifying the phenotype of
type 2 diabetic patients from families with both type 1 and type 2
diabetes.

Shbaklo et al. (2003) evaluated TNFA promoter polymorphisms at positions
-863 (191160.0006) and -1031 and their association with type 1 diabetes
in a group of 210 diabetic patients in Lebanon. Their results showed
that in that population, the C allele is predominant at position -863,
whereas the A allele is rare (2%). At position -1031, however, the C and
T allele distribution was similar in both the patient (17.8% vs 82.2%,
respectively) and the control (21.4% vs 79.6%) groups. No association of
TNFA genotype at position 1031 with type 1 diabetes was found as
demonstrated by the family-based association test and the transmission
disequilibrium test. However, when patient genotypes were compared, the
recessive CC genotype was found in type 1 diabetic males but not in type
1 diabetic females.

- Coronary Heart Disease

From studies of 641 patients with myocardial infarction and 710 control
subjects, Herrmann et al. (1998) concluded that polymorphisms of the
TNFA gene are unlikely to contribute to coronary heart disease risk in
an important way, but that the -308 mutation should be investigated
further in relation to obesity.

- Obesity

Because TNF-alpha expression had been reported to be increased in
adipose tissue of both rodent models of obesity and obese humans, TNFA
was considered a candidate gene for obesity (see 601665). Norman et al.
(1995) scored Pima Indians for genotypes at 3 polymorphic dinucleotide
repeat loci near the TNFA gene. In a sib-pair linkage analysis, the
percentage of body fat, as measured by hydrostatic weighing, was linked
(304 sib pairs, P = 0.002) to the marker closest (10 kb) to TNFA. The
same marker was associated (P = 0.01) by analysis of variants with body
mass index (BMI). To search for DNA variants in TNFA possibly
contributing to obesity, they performed SSCP analysis on the gene from
20 obese and 20 lean subjects. No association could be demonstrated
between alleles at the single polymorphism located in the promoter
region and percent of body fat.

Rosmond et al. (2001) examined the potential impact of the G-to-A
substitution at position -308 of the TNFA gene promoter on obesity and
estimates of insulin, glucose, and lipid metabolism as well as
circulating hormones including salivary cortisol in 284 unrelated
Swedish men born in 1944. Genotyping revealed allele frequencies of 0.77
for allele G and 0.23 for allele A. Tests for differences in salivary
cortisol levels between the TNFA genotypes revealed that, in homozygotes
for the rare allele in comparison with the other genotypes, there were
significantly higher cortisol levels in the morning, before as well as
30 and 60 minutes after stimulation by a standardized lunch. In
addition, homozygotes for the rare allele had a tendency toward higher
mean values of body mass index, waist-to-hip ratio, and abdominal
sagittal diameter compared with the other genotype groups. The results
also indicated a weak trend toward elevated insulin and glucose levels
among men with the A/A genotype. Rosmond et al. (2001) suggested that
the increase in cortisol secretion associated with this polymorphism
might be the endocrine mechanism underlying the previously observed
association between the NcoI TNFA polymorphism and obesity, as well as
insulin resistance.

- Hyperandrogenism

To evaluate the role of TNF-alpha in the pathogenesis of
hyperandrogenism, Escobar-Morreale et al. (2001) evaluated the serum
TNF-alpha levels, as well as several polymorphisms in the promoter
region of the TNF-alpha gene, in a group of 60 hyperandrogenic patients
and 27 healthy controls matched for body mass index. Hyperandrogenic
patients presented with mildly increased serum TNF-alpha levels as
compared with controls. When subjects were classified by body weight,
serum TNF-alpha was increased only in lean patients as compared with
lean controls; this difference was not statistically significant when
comparing obese patients with obese controls. The TNF-alpha gene
polymorphisms studied were equally distributed in hyperandrogenic
patients and controls. However, carriers of the -308A variant presented
with increased basal and leuprolide-stimulated serum androgens and
17-hydroxyprogesterone levels when considering patients and controls as
a group. The authors concluded that the TNF-alpha system might
contribute to the pathogenesis of hyperandrogenism.

- Septic Shock

De Groof et al. (2002) evaluated the GH (see 139250)/IGF1 (147440) axis
and the levels of IGF-binding proteins (IGFBPs), IGFBP3 protease
(146732), glucose, insulin (176730), and cytokines in 27 children with
severe septic shock due to meningococcal sepsis during the first 3 days
after admission. The median age was 22 months. Nonsurvivors had
extremely high GH levels that were significantly different compared with
mean GH levels in survivors during a 6-hour GH profile. Significant
differences were found between nonsurvivors and survivors for the levels
of total IGF1, free IGF1, IGFBP1, IGFBP3 protease activity, IL6
(147620), and TNFA. The pediatric risk of mortality score correlated
significantly with levels of IGFBP1, IGFBP3 protease activity, IL6, and
TNFA and with levels of total IGF1 and free IGF1. Levels of GH and
IGFBP1 were extremely elevated in nonsurvivors, whereas total and free
IGF1 levels were markedly decreased and were accompanied by high levels
of the cytokines IL6 and TNFA.

Mira et al. (1999) reported the results of a multicenter case-control
study of the frequency of the -308G-A polymorphism, which they called
the TNF2 allele, in patients with septic shock. Eighty-nine patients
with septic shock and 87 healthy unrelated blood donors were studied.
Mortality among patients with septic shock was 54%. The polymorphism
frequencies of the controls and patients differed only at the TNF2
allele (39% vs 18% in the septic shock and control groups, respectively,
P = 0.002). Among the septic shock patients, TNF2 polymorphism frequency
was significantly greater among those who had died (52% vs 24% in the
survival group, P = 0.008). Concentrations of TNF-alpha were higher with
TNF2 (68%) than with TNF1 (52%), but their median values were not
statistically different. Mira et al. (1999) estimated that patients with
the TNF2 allele had a 3.7-fold risk of death.

- Cerebral Malaria

Because fatal cerebral malaria is associated with high circulating
levels of tumor necrosis factor-alpha, McGuire et al. (1994) undertook a
large case-control study in Gambian children. The study showed that
homozygotes for the TNF2 allele, a variant of the TNFA gene promoter
region (Wilson et al., 1992), had a relative risk of 7 for death or
severe neurologic sequelae due to cerebral malaria. Although the TNF2
allele is in linkage disequilibrium with several neighboring HLA
alleles, McGuire et al. (1994) showed that this disease association was
independent of HLA class I and class II variation. The data suggested
that regulatory polymorphisms of cytokine genes can affect the outcome
of severe infection. The maintenance of the TNF2 allele at a gene
frequency of 0.16 in The Gambia implies that the increased risk of
cerebral malaria in homozygotes is counterbalanced by some biologic
advantage.

Hill (1999) reviewed the genetic basis of susceptibility and resistance
to malaria, and tabulated 10 genes that are known to affect
susceptibility or resistance to Plasmodium falciparum and/or Plasmodium
vivax. He noted that the association of an upregulatory variant of the
TNF gene promoter (Wilson et al., 1997) with cerebral malaria (McGuire
et al., 1994) had encouraged the assessment of agents that might reduce
the activity of this cytokine (van Hensbroek et al., 1996).

Through systematic DNA fingerprinting of the TNF promoter region, Knight
et al. (1999) identified a SNP that causes the helix-turn-helix
transcription factor OCT1 (POU2F1; 164175) to bind to a novel region of
complex protein-DNA interactions and alters gene expression in human
monocytes. The OCT1-binding genotype, found in approximately 5% of
Africans, was associated with 4-fold increased susceptibility to
cerebral malaria in large studies comparing cases and controls in West
African and East African populations, after correction for other known
TNF polymorphisms and linked HLA alleles. See 191160.0003.

- Alopecia Areata

Galbraith and Pandey (1995) studied 2 polymorphic systems of tumor
necrosis factor-alpha in 50 patients with alopecia areata (104000). The
first biallelic TNFA polymorphism was detected in humans by Wilson et
al. (1992); this involved a single base change from G to A at position
-308 in the promoter region of the gene (191160.0004). The less common
allele, A at -308 (called T2), shows an increased frequency in patients
with IDDM, but this depends on the concurrent increase in HLA-DR3 with
which T2 is associated. A second TNFA polymorphism, described by
D'Alfonso and Richiardi (1994), also involves a G-to-A transition at
position -238 of the gene. In alopecia areata, Galbraith and Pandey
(1995) found that the distribution of T1/T2 phenotypes differed between
patients with the patchy form of the disease and patients with
totalis/universalis disease. There was no significant difference in the
distribution of the phenotypes for the second system. The results
suggested genetic heterogeneity between the 2 forms of alopecia areata
and suggested that the TNFA gene is a closely linked locus within the
major histocompatibility complex on chromosome 6 where this gene maps
and may play a role in the pathogenesis of the patchy form of the
disease.

- Rheumatoid Arthritis

Mulcahy et al. (1996) determined the inheritance of 5 microsatellite
markers from the TNF region in 50 multiplex rheumatoid arthritis (RA;
180300) families. Overall, 47 different haplotypes were observed. One of
these was present in 35.3% of affected, but in only 20.5% of unaffected,
individuals (P less than 0.005). This haplotype accounted for 21.5% of
the parental haplotypes transmitted to affected offspring and only 7.3%
of the haplotypes not transmitted to affected offspring (P = 0.0003).
Further study suggested that the tumor necrosis factor--lymphotoxin
(TNF-LT) region influences susceptibility to RA, distinct from HLA-DR.
The study illustrated the use of the transmission disequilibrium test
(TDT) as described by Spielman et al. (1993).

- Osteoporosis and Osteopenia

Ota et al. (2000) tested 192 sib pairs of adult Japanese women from 136
families for genetic linkage between osteoporosis and osteopenia
phenotypes and allelic variants at the TNFA locus, using a dinucleotide
repeat polymorphism located near the gene. The TNFA locus showed
evidence for linkage to osteoporosis, with mean allele sharing of 0.478
(P = 0.30) in discordant pairs and 0.637 (P = 0.001) in concordant
affected pairs. Linkage with osteopenia was also significant in
concordant affected pairs (P = 0.017). Analyses limited to the
postmenopausal women in their cohort showed similar or even stronger
linkage for both phenotypes.

- Asthma

Winchester et al. (2000) studied the association of the -308G-A variant
of the TNFA gene and the insertion/deletion variant of
angiotensin-converting enzyme (ACE; 106180) with a self-reported history
of childhood asthma in 2 population groups. The -308A allele was
significantly associated with self-reported childhood asthma in the
UK/Irish population but not in the South Asian population. The ACE DD
genotype was not associated with childhood asthma in either population.
Thus, either the -308A allele or a linked major histocompatibility
complex variant may be a genetic risk factor for childhood asthma in the
UK/Irish sample.

- Inflammatory Bowel Diseases

Koss et al. (2000) found that women but not men with extensive compared
to distal colitis (see IBD3, 604519) were significantly more likely to
bear the -308G-A promoter polymorphism of the TNF gene (191160.0004).
The association was even stronger in women who also had an A rather than
a C at position 720 in the LTA gene (153440). These polymorphisms were
also associated with significantly higher TNF production in patients
with Crohn disease, whereas an A instead of a G at position -238 in the
TNF gene was associated with lower production of TNF in patients with
ulcerative colitis.

For additional discussion of an association between variation in the TNF
gene and inflammatory bowel disease, see IBD3 (604519).

- Hepatitis B

To investigate whether TNF-alpha promoter polymorphisms are associated
with clearance of hepatitis B virus (HBV) infection, Kim et al. (2003)
genotyped 1,400 Korean subjects, 1,109 of whom were chronic HBV carriers
and 291 who spontaneously recovered. The TNF promoter alleles that were
previously reported to be associated with higher plasma levels (presence
of -308A or the absence of -863A alleles), were strongly associated with
the resolution of HBV infection. Haplotype analysis revealed that
TNF-alpha haplotype 1 (-1031T; -863C; -857C; -308G; -238G; -163G) and
haplotype 2 (-1031C; -863A; -857C; -308G; -238G; -163G) were
significantly associated with HBV clearance, showing protective antibody
production and persistent HBV infection, respectively (P = 0.003-0.02).

- Cystic Fibrosis

Buranawuti et al. (2007) determined the TNF-alpha-238 and -308 genotypes
in 3 groups of patients with cystic fibrosis (CF; 219700): 101 children
under 17 years of age, 115 adults, and 38 nonsurviving adults (21
deceased and 17 lung transplant after 17 years of age). Genotype
frequencies among adults and children with CF differed for TNF-alpha-238
(G/G vs G/A, p = 0.022), suggesting that TNF-alpha-238 G/A is associated
with an increased chance of surviving beyond 17 years of age. When
adults with CF were compared to nonsurviving adults with CF, genotype
frequencies again differed (TNF-alpha 238 G/G vs G/A, p = 0.0015), and
the hazard ratio for TNF-alpha-238 G/G versus G/A was 0.25. Buranawuti
et al. (2007) concluded that the TNF-alpha-238 G/A genotype appears to
be a genetic modifier of survival in patients with CF.

- Role in HLA-B27-Associated Uveitis

In a study of 114 Caucasian patients with HLA-B27-associated uveitis
compared with 63 healthy unrelated HLA-B27-positive blood donors and 88
healthy unrelated HLA-B27-negative individuals, El-Shabrawi et al.
(2006) found that the frequencies of the TNF-alpha -308GA and -238GA
genotypes were significantly lower in patients with HLA-B27-associated
uveitis (6.1% and 0%, respectively) when compared with the
HLA-B27-negative group, 23% at -308 (p = 0.003), and 7.9% at -238 (p =
0.0003). The frequency of the -238GA genotype was also significantly
lower in patients than among the healthy HLA-B27-positive group. The
authors concluded that HLA-B27-positive individuals show a higher
susceptibility towards development of intraocular inflammation in the
presence of an A allele at nucleotide -238, and to a lesser degree, at
nucleotide -308 of the TNF-alpha gene promoter.

GENE STRUCTURE

Nedwin et al. (1985) determined that TNFA and LTA genes have similar
structures; each spans about 3 kb and contains 4 exons. Only the last
exons of these genes, which code more than 80% of the secreted protein,
are significantly homologous (56%).

MAPPING

By analysis of human-mouse somatic cell hybrids, Nedwin et al. (1985)
found that TNFA and TNFB are closely linked on chromosome 6. Study of
hybrid cells made with rearranged human chromosome 6 showed that both
TNFA and TNFB map to the 6p23-q12 segment. Nedwin et al. (1985)
speculated that close situation of these 2 loci to HLA 'may be useful
for a coordinate regulation of immune system gene products.' By Southern
blot analysis of a panel of major histocompatibility complex deletion
mutants, Spies et al. (1986) established that TNFA and TNFB are closely
linked and situated in the MHC either between HLA-DR (see 142860) and
HLA-A (142800) or centromeric of HLA-DP (see 142858). By in situ
hybridization, they assigned TNFA and TNFB to 6p21.3-p21.1. By pulsed
field gel electrophoresis, Carroll et al. (1987) showed that the TNF
genes are located 200 kb centromeric of HLA-B (142830) and about 350 kb
telomeric of the class I cluster. The TNFA and TNFB genes are separated
by 1 to 2 kb of DNA. By hybridization to fragments of NruI-digested DNA,
Ragoussis et al. (1988) demonstrated that the TNFA/TNFB genes lie
between C2 of class III and HLA-B of class I.

Nedospasov et al. (1986) showed that, in the mouse, TNFA and TNFB are
likewise tandemly arranged and situated on chromosome 17, which bears
much homology of synteny with chromosome 6 of man. Muller et al. (1987)
mapped both tumor necrosis factor and lymphotoxin close to H-2D in the
mouse major histocompatibility complex on chromosome 14. By pulsed field
gel electrophoresis, Inoko and Trowsdale (1987) showed that the human
TNFA and TNFB genes are linked to the HLA-B locus, analogous to their
position in the mouse, where they are located between the class III
region and H-2D. However, the distance between the TNF genes and the
class I region was much greater in man, namely, about 260 kb, compared
to 70 kb in the mouse.

As noted, the region spanning the tumor necrosis factor (TNF) cluster in
the human major histocompatibility complex (MHC) has been implicated in
susceptibility to numerous immunopathologic diseases, including type 1
diabetes mellitus (IDDM; 222100) and rheumatoid arthritis (180300).
However, strong linkage disequilibrium across the MHC has hampered the
identification of the precise genes involved. In addition, the
observation of 'blocks' of DNA in the MHC within which recombination is
very rare limits the resolution that may be obtained by genotyping
individual SNPs. To gain a greater understanding of the haplotypes of
the block spanning the TNF cluster, Allcock et al. (2004) genotyped 32
HLA-homozygous cell lines and 300 healthy control samples for 19 coding
and promoter region SNPs spanning 45 kb in the central MHC near the TNF
genes. The workshop cell lines defined 11 SNP haplotypes that account
for approximately 80% of the haplotypes observed in the 300 control
individuals. Using the control individuals, they defined a further 6
haplotypes that account for an additional 10% of donors. They showed
that the 17 haplotypes of the 'TNF block' can be identified using 15
SNPs.

The TNF block studied by Allcock et al. (2004) includes the TNF genes
(TNFA; LTA, 153440; and LTB, 600978), as well as AIF1 (601833), the
activating NK receptor NCR3 (611550), NFKBIL1 (601022), ATP6P1G
(606853), and BAT1 (142560).

HISTORY

Old (1985) recounted the series of observations, experiments and
discoveries that led up to definition of human TNF and cloning of the
gene. He referred to cloning as 'an important rite of passage for
biological factors such as TNF, and there is a growing sense that a
factor has to be cloned before it is taken very seriously.' He
paraphrased Descartes: 'It's been cloned, therefore it exists.'

Feldmann and Maini (2010) reviewed the findings that led to targeting of
TNF in the treatment of rheumatoid arthritis and other chronic diseases
and offered an appreciation of the role of cytokines in medicine.

ANIMAL MODEL

Bruce et al. (1996) used targeted gene disruption to generate mice
lacking either the p55 (TNFRSF1A; 191190) or the p75 TNF receptors; mice
lacking both p55 and p75 were generated from crosses of the singly
deficient mice. The TNFR-deficient (TNFR-KO) mice exhibited no overt
phenotype under unchallenged conditions. Bruce et al. (1996) reported
that damage to neurons caused by focal cerebral ischemia and epileptic
seizures was exacerbated in the TNFR-KO mice, indicating that TNF serves
a neuroprotective function. Their studies indicated that TNF protects
neurons by stimulating antioxidative pathways. Injury-induced microglial
activation was suppressed in TNFR-KO mice. They concluded that drugs
which target TNF signaling pathways may prove beneficial in treating
stroke or traumatic brain injury.

Marino et al. (1997) generated knockout mice deficient in TNF and
characterized the response of these mice to a variety of inflammatory,
infectious, and antigenic stimuli.

Uysal et al. (1997) generated obese mice with a targeted null mutation
in the genes for Tnf and its p55 and p75 receptors. The absence of TNF
resulted in significantly improved insulin sensitivity in both
diet-induced obesity and the ob/ob (see 164160) model of obesity.
Tnf-deficient mice had lower levels of circulating free fatty acids and
were protected from the obesity-related reduction in insulin receptor
signaling in muscle and fat tissues. Uysal et al. (1997) concluded that
TNF is an important mediator of insulin resistance in obesity through
its effects on several important sites of insulin action.

Roach et al. (2002) noted that TNF is essential for the formation and
maintenance of granulomas and for resistance against infection with
Mycobacterium tuberculosis. Mice lacking Tnf mount a delayed chemokine
response associated with a delayed cellular infiltrate. Subsequent
excessive chemokine production and an intense but loose and
undifferentiated cluster of T cells and macrophages, capable of
producing high levels of Ifng in vitro, were unable to protect Tnf -/-
mice from fatal tuberculosis after approximately 28 days, whereas all
wildtype mice survived for at least 16 weeks. Roach et al. (2002)
concluded that TNF is required for the early induction of chemokine
production and the recruitment of cells forming a protective granuloma.
The TNF-independent production of chemokines results in a dysregulated
inflammatory response unable to contain M. tuberculosis, which suggests
a mechanism for the reactivation of clinical tuberculosis observed by
Keane et al. (2001) in patients undergoing treatment for rheumatoid
arthritis (180300) or Crohn disease (see 266600) with a humanized
monoclonal antibody to TNF.

Diwan et al. (2004) compared transgenic mice with targeted cardiac
overexpression of secreted wildtype Tnf to transgenic mice with targeted
cardiac overexpression of a noncleavable transmembrane form of Tnf. Both
lines of mice had overlapping levels of myocardial Tnf protein, but
developed strikingly different cardiac phenotypes: the mice
overexpressing the transmembrane form of Tnf developed concentric left
ventricular hypertrophy, whereas the mice overexpressing secreted Tnf
had dilated left ventricular hypertrophy. Diwan et al. (2004) suggested
that posttranslational processing of TNF by ADAM17 (603639), as opposed
to TNF expression per se, is responsible for the adverse cardiac
remodeling that occurs after sustained TNF overexpression.

Vielhauer et al. (2005) studied immune complex-mediated
glomerulonephritis in Tnfr1- and Tnfr2-deficient mice. Proteinuria and
renal pathology were initially milder in Tnfr1-deficient mice, but at
later time points were similar to those in wildtype controls, with
excessive renal T-cell accumulation and reduced T-cell apoptosis. In
contrast, Tnfr2-deficient mice were completely protected from
glomerulonephritis at all time points, despite an intact immune system
response. Tnfr2 expression on intrinsic renal cells, but not leukocytes,
was essential for glomerulonephritis and glomerular complement
deposition. Vielhauer et al. (2005) concluded that the proinflammatory
and immunosuppressive properties of TNF segregate at the level of its
receptors, with TNFR1 promoting systemic immune responses and renal
T-cell death and intrinsic renal cell TNFR2 playing a critical role in
complement-dependent tissue injury.

In mice, Balosso et al. (2005) found that intrahippocampal injection of
murine Tnfa or astrocytic overexpression of murine Tnfa inhibited the
number and duration of kainate-induced seizures. Transgenic mice lacking
p75 receptors showed increased seizure susceptibility, suggesting that
the protective effect of Tnfa was mediated by p75 receptors.
Immunohistochemical and Western blot analysis identified p75 receptors,
but not p55 receptors, in the mouse hippocampus. The findings indicated
a role for inflammatory pathways in the pathophysiology of seizures.

Both homozygous and heterozygous Tshr (603372)-null mice are osteopenic
with evidence of enhanced osteoclast differentiation. Hase et al. (2006)
found that increased osteoclastogenesis in these mice was rescued with
graded reductions in the dosage of the Tnf gene.

Soller et al. (2007) reported that canine Tnf, Il1a (147760), and Il1b
(147720) have high coding and protein sequence identity to human and
other mammalian homologs. They suggested that dog models of
cytokine-mediated human diseases may be highly informative.

Guo et al. (2008) noted that transgenic mice overexpressing human TNF
exhibit reduced long bone volume, decreased mineralized bone nodule
formation, and arthritis. They showed that TNF overexpression induced
bone loss by increasing expression of Smurf1 (605568), resulting in
ubiquitination and proteasomal degradation of Smad1 (601595) and Runx2
(600211). Deletion of Smurf1 in TNF-transgenic mice prevented systemic
bone loss and improved bone strength.

*FIELD* AV
.0001
TNF RECEPTOR BINDING, ALTERED
TNF, LEU29SER

Van Ostade et al. (1993) identified 2 cell lines with mutations in TNF
that resulted in loss of almost all activity in the standard cytotoxic
assay with the L929 murine fibrosarcoma cell line and were shown to have
lost the binding affinity specifically for the TNF-R55 human receptor
(191190). One of the mutants was found to carry a leu29-to-ser mutation
and the other, an arg32-to-trp mutation (191160.0002). The remarkable
ability of TNF, especially in combination with interferon, selectively
to kill or inhibit malignant cell lines is unmatched by any other
combination of cytokines. However, clinical trials have been
disappointing, and it is estimated that a TNF dose would be effective
only at 5 to 25 times the maximum tolerated dose. TNF binds to 2 types
of receptors: the smaller, TNF-R55, is present on most cells and
particularly on those susceptible to the cytotoxic action of TNF; the
larger, TNF-R75 (191191), is also present on many cell types, especially
those of myeloid origin, and is strongly expressed on stimulated T and B
lymphocytes. The selective binding of the mutant TNF to TNF-R55 might
make it useful in cancer therapy.

.0002
TNF RECEPTOR BINDING, ALTERED
TNF, ARG32TRP

See 191160.0001 and Van Ostade et al. (1993).

.0003
MALARIA, CEREBRAL, SUSCEPTIBILITY TO
TNF, -376G-A

Knight et al. (1999) studied the significance of a single-nucleotide
polymorphism (SNP) in the promoter region of TNF: a substitution of
adenine for guanine at -376. Binding experiments showed that the
transcription factor OCT1 (164175) can bind to site alpha of TNF, but
that this binding is dependent on the presence of the TNF(-376A) allele.
They showed, furthermore, that TNF(-376A) affects TNF expression in
vitro. Since TNF has a pivotal role in human malaria, acting both to
suppress parasitic growth and to cause clinical symptoms, Knight et al.
(1999) investigated frequency of this allele in cases of cerebral
malaria (611162) in the Gambia and in Kenya. They found an odds ratio
(OR) of 4.3 for the -376A allele, compared with the control group. In
both the Kenyan and the Gambian study populations, they found that the
relatively rare -376A allele occurred only in individuals who also
carried the more common -238A allele. The same had been reported in
European populations. These results indicated that the -376 polymorphism
occurred more recently in human evolution than the -238 polymorphism,
and that it arose as a mutation of a haplotype bearing the -238A allele.

.0004
SEPTIC SHOCK, SUSCEPTIBILITY TO
ASTHMA, SUSCEPTIBILITY TO, INCLUDED;;
HUMAN IMMUNODEFICIENCY VIRUS DEMENTIA, SUSCEPTIBILITY TO, INCLUDED;;
MIGRAINE WITHOUT AURA, SUSCEPTIBILITY TO, INCLUDED;;
PSORIATIC ARTHRITIS, SUSCEPTIBILITY TO, INCLUDED;;
SYSTEMIC LUPUS ERYTHEMATOSUS, SUSCEPTIBILITY TO, INCLUDED;;
MALARIA, CEREBRAL, SUSCEPTIBILITY TO, INCLUDED
TNF, -308G-A

Mira et al. (1999) referred to the TNFA promoter polymorphisms at
position -308 as TNF1 for guanine and TNF2 for adenine. In a multicenter
study involving 7 institutions, they found a significant association
between the TNF2 allele and susceptibility to septic shock and death
from septic shock. The septic shock group was defined by the following 6
criteria within a 12-hour period: (1) clinical evidence of infection;
(2) hyperthermia or hypothermia; (3) tachycardia; (4) tachypnea; (5)
necessity for vasopressor to maintain systolic blood pressure; and (6)
evidence of inadequate organ function or perfusion.

Moraes et al. (2001) found that the TNF2 polymorphism is significantly
associated with a stronger response (Mitsuda reaction) to lepromin in
borderline tuberculoid leprosy patients. Epigenetic factors such as a
history of BCG vaccination or a reversal reaction, but not both, were
also associated with boosted Mitsuda reactions. Moraes et al. (2001)
concluded that augmented TNF production may be associated with the TNF2
allele and an increased granulomatous response.

Ma et al. (1998) found a higher frequency of the rare T2 TNFA
polymorphism (-308G-A) in 43 Japanese Guillain-Barre syndrome (139393)
patients who had had antecedent infection with C. jejuni than in 85
community controls.

Witte et al. (2002) evaluated the relation between the -308G-A promoter
polymorphism and risk of asthma (600807) in 236 cases and 275
nonasthmatic controls. Logistic regression analyses indicated that
having 1 or 2 copies of the -308A allele increased the risk of asthma
(odds ratio = 1.58), the magnitude of which was increased when
restricting the cases to those with acute asthma (odds ratio = 1.86, P =
0.04) or further restricting the subjects to those with a family history
of asthma and those of European American ancestry (odds ratio = 3.16, P
= 0.04).

Shin et al. (2004) genotyped 550 Korean asthmatics and 171 Korean
controls at 5 SNPs in TNFA and 2 SNPs in TNFB. Six common haplotypes
could be constructed in the TNF gene cluster. The -308G-A polymorphism
showed a significant association with the risk of asthma (p = 0.0004).
The frequency of the -308A allele-containing genotype in asthmatics
(9.8%) was much lower than that in normal controls (22.9%). The
protective effects of this polymorphism on asthma were also evident in
separated subgroups by atopic status (p = 0.05 in nonatopic subjects and
p = 0.003 in atopic subjects). The most common haplotype of the TNF gene
cluster (TNF-ht1-GGTCCGG) was associated with total serum IgE levels
(147050) in asthma patients, especially in nonatopic patients (p =
0.004). Shin et al. (2004) concluded that genetic variants of TNF may be
involved in the development of asthma and total serum IgE level in
bronchial asthma patients.

Aoki et al. (2006) did not find a significant association between the
TNF -308G-A polymorphism and childhood atopic asthma in 2 independent
Japanese populations; however, metaanalysis of a total of 2,477 asthma
patients and 3,217 control individuals showed that the -308G-A
polymorphism was significantly associated with asthma. The combined odds
ratio was 1.46 for fixed or random effects (p = 0.0000001 and p =
0.00014, respectively).

Quasney et al. (2001) stated that immunologic mechanisms resulting in
macrophage infiltration and glial cell activation in the brain are
thought to be involved in the pathophysiology of HIV dementia. Moreover,
elevated levels of TNF-alpha have been found in the brains of patients
with HIV dementia. In a study of 16 patients with HIV dementia, 45
HIV-infected patients without dementia, and 231 controls, they found an
increased frequency of the -308A allele in patients with HIV dementia
(0.28 vs 0.11 in controls and 0.07 in HIV patients without dementia).
There were no individuals with the A/A genotype in either of the
HIV-infected groups. Quasney et al. (2001) noted that the -308A allele
is associated with higher TNF-alpha secretion in response to an
inflammatory stimulus and that evidence has shown a role for TNF-alpha
in neuronal damage, thus suggesting a genetic predisposition to the
development of HIV dementia.

Cox et al. (1994) reported that the -308A allele has an increased
frequency in type I diabetes mellitus (222100). Krikovszky et al. (2002)
studied ambulatory blood pressure in 126 Hungarian adolescents with type
I diabetes mellitus. They found that the prevalence of the -308A allele
was higher in diabetic adolescents than in the Hungarian reference
population. TNFA genotype was associated with both systolic and
diastolic blood pressure values. The -308A allele carrier state appeared
to be associated with lower systolic and diastolic blood pressure
values.

Szalai et al. (2002) found an increased frequency of the C4B*Q0 allele
(see 120820) in patients with severe coronary artery disease (CAD) who
underwent bypass surgery compared to healthy controls (14.2% vs 9.9%).
Investigation of specific allelic combinations revealed that C4B*Q0 in
combination with the TNF-alpha -308A allele was significantly higher in
CAD patients, particularly those with preoperative myocardial
infarction.

In a study of 147 patients with psoriatic arthritis (607507) and 389
controls, Balding et al. (2003) found that the -308A allele was
significantly associated with both the presence and progression of joint
erosions in psoriatic arthritis, and that the AA genotype was associated
with the lowest mean age at onset of psoriasis (p = 0.0081).

In a group of 261 patients with migraine without aura (see, e.g.,
157300), Rainero et al. (2004) found that the G/G genotype was
associated with an increased risk of migraine (odds ratio of 3.30).
Rainero et al. (2004) suggested that TNF-alpha may be involved in the
pathogenesis of migraine, perhaps due to its effect on cerebral blood
flow; alternatively, a closely linked locus may be involved.

In a metaanalysis of 19 studies, Lee et al. (2006) found an association
between the -308A/A genotype and the -308A allele and systemic lupus
erythematosus (SLE; 152700) in European-derived population (odds ratio
of 4.0 for A/A and 2.1 for the A allele), but not in Asian-derived
populations.

.0005
VASCULAR DEMENTIA, SUSCEPTIBILITY TO
ALZHEIMER DISEASE, SUSCEPTIBILITY TO, INCLUDED
TNF, -850C-T

McCusker et al. (2001) typed the -850C-T polymorphism (dbSNP rs1799724)
in 242 patients with sporadic Alzheimer disease (104300), 81 patients
with vascular dementia, 61 stroke patients without dementia, and 235
normal controls. The distribution of TNF-alpha genotypes in the vascular
dementia group differed significantly from that in the stroke and normal
control groups, giving an odds ratio of 2.51 (95% CI, 1.49-4.21) for the
development of vascular dementia for individuals with a CT or TT
genotype. Logistic regression analysis indicated that possession of the
T allele significantly increased the risk of Alzheimer disease
associated with the APOE4 (see 107741) allele (odds ratio of 2.73
(1.68-4.44) for those with APOE4 and without TNF T, vs 4.62 (2.38-8.96)
for those with APOE4 and TNF T).

Among 506 AD patients, Laws et al. (2005) found that presence of the
-850 T allele conferred an odds ratio of 1.63 for disease development.
Presence of the APOE4 allele and the T allele increased the odds ratio
to 6.65, suggesting a synergistic effect. In addition, presence of the
-850 T allele was associated with lower levels of CSF beta-amyloid-42 in
patients with AD.

.0006
ALZHEIMER DISEASE, PROTECTION AGAINST
TNF, -863C-A

Skoog et al. (1999) studied the -863C-A promoter polymorphism of the TNF
gene and found that the rare A allele associated with 31% lower
transcriptional activity in human hepatoblastoma cells. Among 254
Swedish men, allele frequencies were 0.83 and 0.17 for the C and A
alleles, respectively. Carriers of the A allele had significantly
decreased serum TNF-alpha concentrations compared to carriers of the C
allele. Electromobility shift assays showed that the -863A allele was
associated with decreased binding of monocytic and hepatic nuclear
factors to the promoter region of the TNF gene.

In a study of 265 patients with late-onset Alzheimer disease (AD;
104300) and 347 controls, Ramos et al. (2006) found an association
between the -863A allele and decreased risk for disease development. The
-863A allele was present in 16.9% of controls and 12.6% of patients.
Comparison of the 3 genotypes (C/C, C/A, and A/A) suggested a
dose-response effect with the A/A genotype conferring an odds ratio of
0.58. The findings supported a role for inflammation in AD.

*FIELD* SA
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*FIELD* CN
Paul J. Converse - updated: 01/30/2014
Ada Hamosh - updated: 3/21/2013
Ada Hamosh - updated: 11/22/2011
Paul J. Converse - updated: 2/9/2011
Paul J. Converse - updated: 10/8/2010
Patricia A. Hartz - updated: 9/21/2010
Ada Hamosh - updated: 8/24/2010
Marla J. F. O'Neill - updated: 10/22/2008
Patricia A. Hartz - updated: 8/15/2008
Paul J. Converse - updated: 5/19/2008
Jane Kelly - updated: 11/28/2007
Paul J. Converse - updated: 9/25/2007
Paul J. Converse - updated: 8/7/2007
Ada Hamosh - updated: 6/20/2007
Marla J. F. O'Neill - updated: 6/7/2007
Ada Hamosh - updated: 12/6/2006
George E. Tiller - updated: 12/4/2006
Cassandra L. Kniffin - updated: 11/9/2006
Marla J. F. O'Neill - updated: 10/24/2006
Patricia A. Hartz - updated: 10/6/2006
Ada Hamosh - updated: 8/1/2006
Cassandra L. Kniffin - updated: 4/5/2006
Victor A. McKusick - updated: 1/30/2006
Ada Hamosh - updated: 1/11/2006
Paul J. Converse - updated: 1/10/2006
Marla J. F. O'Neill - updated: 11/11/2005
Paul J. Converse - updated: 10/31/2005
George E. Tiller - updated: 10/21/2005
Cassandra L. Kniffin - updated: 8/19/2005
Marla J. F. O'Neill - updated: 7/21/2005
Jane Kelly - updated: 6/23/2005
Marla J. F. O'Neill - updated: 5/20/2005
Marla J. F. O'Neill - updated: 5/10/2005
Stylianos E. Antonarakis - updated: 3/29/2005
Marla J. F. O'Neill - updated: 3/16/2005
Victor A. McKusick - updated: 1/10/2005
George E. Tiller - updated: 1/6/2005
Cassandra L. Kniffin - updated: 11/11/2004
Paul J. Converse - updated: 10/15/2004
Cassandra L. Kniffin - updated: 9/1/2004
Paul J. Converse - updated: 1/30/2004
Victor A. McKusick - updated: 1/9/2004
Ada Hamosh - updated: 10/29/2003
Cassandra L. Kniffin - updated: 10/17/2003
John A. Phillips, III - updated: 10/3/2003
Paul J. Converse - updated: 8/5/2003
Cassandra L. Kniffin - updated: 5/29/2003
Denise L. M. Goh - updated: 4/21/2003
Victor A. McKusick - updated: 3/26/2003
George E. Tiller - updated: 2/13/2003
John A. Phillips, III - updated: 1/6/2003
Victor A. McKusick - updated: 12/26/2002
Cassandra L. Kniffin - updated: 12/18/2002
Michael B. Petersen - updated: 8/30/2002
Victor A. McKusick - updated: 5/23/2002
Victor A. McKusick - updated: 5/21/2002
Ada Hamosh - updated: 3/26/2002
John A. Phillips, III - updated: 2/28/2002
John A. Phillips, III - updated: 8/13/2001
Ada Hamosh - updated: 4/30/2001
Paul J. Converse - updated: 4/25/2001
John A. Phillips, III - updated: 3/9/2001
Paul J. Converse - updated: 2/5/2001
Victor A. McKusick - updated: 12/18/2000
Victor A. McKusick - updated: 3/15/2000
John A. Phillips, III - updated: 2/25/2000
Victor A. McKusick - updated: 1/12/2000
John A. Phillips, III - updated: 11/18/1999
Victor A. McKusick - updated: 9/15/1999
Orest Hurko - updated: 8/25/1999
Victor A. McKusick - updated: 5/26/1999
Victor A. McKusick - updated: 10/6/1998
Victor A. McKusick - updated: 9/2/1997
Moyra Smith - updated: 8/27/1996

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
mgross: 01/30/2014
carol: 9/6/2013
carol: 4/3/2013
alopez: 4/2/2013
carol: 4/1/2013
terry: 3/21/2013
alopez: 3/9/2012
terry: 1/17/2012
alopez: 11/30/2011
terry: 11/22/2011
mgross: 2/9/2011
mgross: 10/8/2010
terry: 10/8/2010
mgross: 9/21/2010
mgross: 8/31/2010
terry: 8/24/2010
carol: 4/27/2010
terry: 6/3/2009
carol: 10/22/2008
mgross: 8/19/2008
terry: 8/15/2008
carol: 8/14/2008
mgross: 5/19/2008
carol: 11/28/2007
mgross: 10/24/2007
mgross: 9/27/2007
terry: 9/25/2007
mgross: 8/23/2007
terry: 8/7/2007
mgross: 7/5/2007
terry: 6/20/2007
carol: 6/20/2007
wwang: 6/13/2007
terry: 6/7/2007
terry: 5/7/2007
alopez: 12/13/2006
terry: 12/6/2006
wwang: 12/4/2006
terry: 12/4/2006
wwang: 11/10/2006
ckniffin: 11/9/2006
wwang: 10/24/2006
terry: 10/24/2006
wwang: 10/11/2006
terry: 10/6/2006
wwang: 10/2/2006
ckniffin: 9/29/2006
alopez: 8/3/2006
terry: 8/1/2006
wwang: 4/7/2006
ckniffin: 4/5/2006
alopez: 2/7/2006
terry: 1/30/2006
alopez: 1/12/2006
terry: 1/11/2006
mgross: 1/10/2006
wwang: 11/11/2005
alopez: 10/31/2005
alopez: 10/21/2005
carol: 9/23/2005
ckniffin: 9/7/2005
wwang: 8/29/2005
ckniffin: 8/19/2005
wwang: 7/25/2005
terry: 7/21/2005
alopez: 6/23/2005
wwang: 5/23/2005
terry: 5/20/2005
wwang: 5/18/2005
wwang: 5/10/2005
mgross: 3/29/2005
wwang: 3/17/2005
wwang: 3/16/2005
terry: 3/16/2005
alopez: 2/15/2005
terry: 1/10/2005
alopez: 1/6/2005
ckniffin: 11/11/2004
mgross: 10/15/2004
carol: 9/7/2004
ckniffin: 9/1/2004
alopez: 2/18/2004
mgross: 1/30/2004
tkritzer: 1/9/2004
terry: 1/9/2004
alopez: 10/30/2003
terry: 10/29/2003
carol: 10/19/2003
ckniffin: 10/17/2003
alopez: 10/3/2003
cwells: 8/5/2003
tkritzer: 6/9/2003
ckniffin: 5/29/2003
tkritzer: 5/7/2003
carol: 4/30/2003
carol: 4/21/2003
carol: 4/2/2003
tkritzer: 3/27/2003
terry: 3/26/2003
cwells: 2/13/2003
alopez: 1/6/2003
carol: 1/2/2003
tkritzer: 12/27/2002
terry: 12/26/2002
carol: 12/26/2002
tkritzer: 12/23/2002
ckniffin: 12/18/2002
cwells: 8/30/2002
cwells: 6/4/2002
terry: 5/23/2002
terry: 5/21/2002
alopez: 3/26/2002
terry: 3/26/2002
alopez: 2/28/2002
carol: 1/3/2002
alopez: 8/13/2001
mcapotos: 5/7/2001
terry: 4/30/2001
mgross: 4/25/2001
carol: 3/19/2001
joanna: 3/15/2001
alopez: 3/9/2001
mgross: 2/5/2001
cwells: 1/24/2001
mcapotos: 1/18/2001
mcapotos: 1/5/2001
terry: 12/18/2000
alopez: 9/29/2000
mgross: 3/15/2000
mgross: 2/25/2000
mgross: 2/2/2000
terry: 1/12/2000
alopez: 11/18/1999
carol: 10/6/1999
jlewis: 9/28/1999
terry: 9/15/1999
carol: 8/25/1999
terry: 6/9/1999
alopez: 5/27/1999
terry: 5/26/1999
carol: 10/7/1998
terry: 10/6/1998
terry: 6/1/1998
jenny: 9/8/1997
terry: 9/2/1997
terry: 11/13/1996
terry: 9/25/1996
mark: 9/11/1996
mark: 8/27/1996
mark: 2/13/1996
mark: 7/30/1995
mimadm: 6/7/1995
carol: 12/7/1994
terry: 4/27/1994
carol: 2/10/1993
carol: 2/5/1993

MIM 607507
*RECORD*
*FIELD* NO
607507
*FIELD* TI
#607507 PSORIATIC ARTHRITIS, SUSCEPTIBILITY TO
PSORIATIC ARTHRITIS, SUSCEPTIBILITY TO, 1; PSORAS1
read more*FIELD* TX
A number sign (#) is used with this entry because of evidence that
susceptibility to psoriatic arthritis is determined by multiple genes as
demonstrated by the strong association between psoriasis/psoriatic
arthritis and HLA-Cw*0602 (see HLA-C, 142840) and between psoriatic
arthritis and sequence variants of the NOD2/CARD15 (605956), TNFA
(191160), and LTA (153440) genes.

DESCRIPTION

Psoriasis (177900) is a chronic inflammatory skin disease that may have
an autoimmune basis. The disorder has a strong but complex genetic
basis, with a concordance rate of 50 to 70% among monozygotic twins.
Psoriatic arthritis affects more than 10% of patients with psoriasis
and, in most cases, there is an association between the severity of the
arthritis and the skin involvement (Gudjonsson et al., 2002).

MAPPING

Psoriatic arthritis is somewhat more common in HLA-Cw6-negative patients
than in Cw6-positive ones (Gudjonsson et al., 2002). The association of
psoriatic arthritis with HLA-Cw*0602 is less profound than the
association of psoriasis and HLA-Cw*0602 and is most evident in patients
with psoriatic arthritis with early onset of arthritis (Enerback et al.,
1997; Gladman et al., 1999).

In Iceland, Karason et al. (2003) identified 178 patients with psoriatic
arthritis out of 906 patients (about 20%) who were included in a genetic
study of psoriasis. Using a comprehensive genealogy database, they were
able to connect 100 of these into 39 families. They genotyped the
patients using a framework marker set of 1,000 microsatellite markers,
with an average density of 3 cM, and performed multipoint,
affected-only, allele-sharing linkage analysis. On the basis of the
initial results, they genotyped more markers for the most prominent
loci. Linkage with a lod score of 2.17 was observed on 16q. The linkage
analysis, conditioned on paternal transmission to affected individuals,
gave a lod score of 4.19, whereas a lod score of only 1.03 was observed
when conditioned for maternal transmission. The data indicated that a
gene on 16q may be involved in paternal transmission of psoriatic
arthritis.

In studies of psoriatic arthritis in Newfoundland, Rahman et al. (2003)
found a strong association between 3 independent variants in the
NOD2/CARD15 gene.

In blood samples from patients with psoriatic arthritis, Ritchlin et al.
(2003) observed a marked increase in osteoclast precursors compared to
those from healthy controls. Peripheral blood mononuclear cells from
patients readily formed osteoclasts in vitro and spontaneously secreted
higher levels of TNF-alpha than did those from healthy controls. In
vivo, osteoclast precursor frequency declined substantially in patients
following treatment with anti-TNF agents. Immunohistochemical analysis
of subchondral bone and synovium revealed TNFRSF11A (603499)-positive
perivascular mononuclear cells and osteoclasts in patient specimens.
TNFSF11 (602642) expression was dramatically upregulated in the synovial
lining layer, whereas TNFRSF11B (602643) immunostaining was restricted
to the endothelium. Ritchlin et al. (2003) suggested a model for the
pathogenesis of the aggressive bone erosions seen in psoriatic
arthritis: osteoclast precursors arise from TNF-alpha-activated
peripheral bone marrow cells that migrate to the inflamed synovium and
subchondral bone, where they are exposed to unopposed TNFSF11 and
TNF-alpha, resulting in osteoclastogenesis at the erosion front and in
subchondral bone, which results in a bidirectional assault on psoriatic
bone.

In a study of 147 patients with psoriatic arthritis and 389 controls,
Balding et al. (2003) found that the TNF-alpha -308G-A (191160.0004) and
TNF-beta +252A-G (153440.0002) polymorphisms were significantly
associated with age at psoriasis onset and with the presence and
progression of joint erosions in psoriatic arthritis. The authors
suggested that TNF gene polymorphisms may be useful prognostic markers
in psoriatic arthritis.

By SNP analysis, Giardina et al. (2006) excluded linkage to the PSORS2
locus (602723) on chromosome 17q25 in 245 Italian patients with
psoriatic arthritis.

Huffmeier et al. (2009) analyzed 4 variants in the IL12B (161561) and
IL23R (607562) genes in 748 patients with psoriatic arthritis, 1,114
patients with psoriasis, and 937 controls. Variations in both genes had
previously been associated with psoriasis; see PSORS7 (605606) and
PSORS11 (612599). In the study, the strongest associations in both
disease groups were found with IL12B variants dbSNP rs3212227 and dbSNP
rs6887695 (p values ranging between 2.10 x 10(-5) and 9.67 x 10(-7) with
corresponding odds ratios of 1.43 to 1.50). The IL12B risk haplotype
also showed an association in both groups (p value on the order of
10(-6)). The effect for dbSNP rs11209026 in the IL23R gene was slightly
weaker for psoriasis (p = 2.42 x 10(-6)) and psoriatic arthritis (p =
0.002). The findings confirmed previous studies that variants in the
IL12B and IL23R genes are susceptibility factors for psoriasis, and
extended the findings to psoriatic arthritis.

*FIELD* RF
1. Balding, J.; Kane, D.; Livingstone, W.; Mynett-Johnson, L.; Bresnihan,
B.; Smith, O.; FitzGerald, O.: Cytokine gene polymorphisms: association
with psoriatic arthritis susceptibility and severity. Arthritis Rheum. 48:
1408-1413, 2003.

2. Enerback, C.; Martinsson, T.; Inerot, A.; Wahlstrom, J.; Enlund,
F.; Yhr, M.; Samuelsson, L.; Swanbeck, G.: Significantly earlier
age at onset for the HLA-Cw6-positive than for the Cw6-negative psoriatic
sibling. (Letter) J. Invest. Derm. 109: 695-696, 1997.

3. Giardina, E.; Predazzi, I.; Sinibaldi, C.; Peconi, C.; Amerio,
P.; Costanzo, A.; Paradisi, A.; Capizzi, R.; Paradisi, M.; Chimenti,
S.; Taccari, E.; Novelli, G.: PSORS2 markers are not associated with
psoriatic arthritis in the Italian population. Hum. Hered. 61: 120-122,
2006.

4. Gladman, D. D.; Cheung, C.; Ng, C.-M.; Wade, J. A.: HLA-C locus
alleles in patients with psoriatic arthritis (PsA). Hum. Immun. 60:
259-261, 1999.

5. Gudjonsson, J. E.; Karason, A.; Antonsdottir, A. A.; Runarsdottir,
E. H.; Gulcher, J. R.; Stefansson, K.; Valdimarsson, H.: HLA-Cw6-positive
and HLA-Cw6-negative patients with psoriasis vulgaris have distinct
clinical features. J. Invest. Derm. 118: 362-365, 2002.

6. Huffmeier, U.; Lascorz, J.; Bohm, B.; Lohmann, J.; Wendler, J.;
Mossner, R.; Reich, K.; Traupe, H.; Kurrat, W.; Burkhardy, H.; Reis,
A.: Genetic variants of the IL-23R pathway: association with psoriatic
arthritis and psoriasis vulgaris, but no specific risk factor for
arthritis. J. Invest. Derm. 129: 355-358, 2009.

7. Karason, A.; Gudjonsson, J. E.; Upmanyu, R.; Antonsdottir, A. A.;
Hauksson, V. B.; Runasdottir, E. H.; Jonsson, H. H.; Gudbjartsson,
D. F.; Frigge, M. L.; Kong, A.; Stefansson, K.; Valdimarsson, H.;
Gulcher, J. R.: A susceptibility gene for psoriatic arthritis maps
to chromosome 16p: evidence for imprinting. Am. J. Hum. Genet. 72:
125-131, 2003.

8. Rahman, P.; Bartlett, S.; Siannis, F.; Pellett, F. J.; Farewell,
V. T.; Peddle, L.; Schentag, C. T.; Alderdice, C. A.; Hamilton, S.;
Khraishi, M.; Tobin, Y.; Hefferton, D.; Gladman, D. D.: CARD15: a
pleiotropic autoimmune gene that confers susceptibility to psoriatic
arthritis. Am. J. Hum. Genet. 73: 677-681, 2003.

9. Ritchlin, C. T.; Haas-Smith, S. A.; Li, P.; Hicks, D. G.; Schwarz,
E. M.: Mechanisms of TNF-alpha- and RANKL-mediated osteoclastogenesis
and bone resorption in psoriatic arthritis. J. Clin. Invest. 111:
821-831, 2003.

*FIELD* CN
Cassandra L. Kniffin - updated: 8/3/2009
Cassandra L. Kniffin - updated: 7/12/2006
Marla J. F. O'Neill - updated: 5/18/2005
Marla J. F. O'Neill - updated: 2/7/2005
Victor A. McKusick - updated: 9/5/2003

*FIELD* CD
Victor A. McKusick: 1/24/2003

*FIELD* ED
carol: 08/04/2009
ckniffin: 8/3/2009
wwang: 1/23/2007
wwang: 7/14/2006
ckniffin: 7/12/2006
wwang: 3/27/2006
wwang: 5/18/2005
tkritzer: 2/8/2005
terry: 2/7/2005
terry: 11/3/2004
alopez: 9/8/2003
terry: 9/5/2003
alopez: 1/24/2003

MIM 610424
*RECORD*
*FIELD* NO
610424
*FIELD* TI
#610424 HEPATITIS B VIRUS, SUSCEPTIBILITY TO
;;HBV, SUSCEPTIBILITY TO
HEPATITIS B VIRUS, RESISTANCE TO, INCLUDED;;
read moreHBV, RESISTANCE TO, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because variation in several
different genes likely influences susceptibility to hepatitis B virus
(HBV) infection.

DESCRIPTION

HBV is a DNA virus that enters the liver via the bloodstream, and
replication occurs only in liver tissue. Transmission occurs by
percutaneous or mucosal exposure to infected blood or other body fluids.
Approximately one third of all cases of cirrhosis and half of all cases
of hepatocellular carcinoma (HCC; 114550) can be attributed to chronic
HBV infection. Worldwide, 2 billion people have been infected with HBV,
360 million have chronic infection, and 600,000 die each year from
HBV-related liver disease or HCC. However, there is marked geographic
variability in HBV prevalence, with chronic infection affecting less
than 2% of the populations of North America and western and northern
Europe; between 2 and 7% of the populations of eastern and central
Europe, the Amazon basin, the Middle East, and the Indian subcontinent;
and more than 8% of the populations of Asia, sub-Saharan Africa, and the
Pacific (Seeff and Hoofnagle, 2006; Shepard et al., 2006).

CLINICAL FEATURES

HBV infection may result in subclinical or asymptomatic infection, acute
self-limited hepatitis, or fulminant hepatitis requiring liver
transplantation. Persons with acute hepatitis B can show signs and
symptoms that include nausea, abdominal pain, vomiting, fever, jaundice,
dark urine, changes in stool color, and hepatomegaly or splenomegaly.
More than 90% of infected infants, 25 to 50% of children infected
between 1 and 5 years of age, and 6 to 10% of acutely infected older
children and adults develop chronic HBV infection, which can lead to
cirrhosis or HCC. Immunosuppressed persons are also at higher risk of
developing chronic infection. Chronically infected individuals who
develop HBV-related cirrhosis or HCC may be asymptomatic until
diagnosis, or they may encounter periodic signs and symptoms of acute
hepatitis. Extrahepatic complications can also occur, including
polyarteritis nodosa, membranous glomerulonephritis, and
membranoproliferative glomerulonephritis (Shepard et al., 2006).

PATHOGENESIS

- Viral Replication

HBV has only 4 open reading frames, 3 of which encode the capsid,
envelope, and polymerase proteins. The fourth encodes HBX, a poorly
expressed protein required for viral replication (Ganem, 2001). Bouchard
et al. (2001) showed that HBX induces release of calcium into the
cytoplasm, presumably from mitochondria or endoplasmic reticulum. HBX
expression thereby induces activation of PYK2 (PTK2B; 601212), which
activates SRC (190090) and HBV DNA replication. Inhibition of PYK2 or
calcium signaling mediated by mitochondrial calcium channels could block
HBV DNA replication, and enhancement of cytoplasmic calcium was able to
substitute for HBX in stimulating HBV DNA replication.

- Host Immune Response

Using FACS analysis, Wang et al. (2010) found that CD137L (TNFSF9;
606182) expression in peripheral CD14 (158120)-positive monocytes was
significantly higher in patients with chronic hepatitis B than in
healthy controls. Furthermore, CD137L expression in CD14-positive
monocytes was significantly increased in patients with chronic hepatitis
B and liver cirrhosis compared with patients with no cirrhosis. Wang et
al. (2010) found that injection of anti-CD137 (TNFRSF9; 602250), a mimic
of CD137L, in HBV-transgenic mice promoted liver disease progression
from hepatitis to fibrosis, cirrhosis, and, ultimately, liver cancer.
Flow cytometric analysis demonstrated an increase in the percentage of
Cd8 (see 186910)-positive intrahepatic lymphocytes in HBV-transgenic
mice treated with anti-CD137. Depletion of Cd8-positive, Cd4
(186940)-positive, or natural killer cells showed that Cd8-positive T
cells, which were not specific for HBV and produced gamma-interferon
(IFNG; 147570), were the main mediators of liver fibrosis induced by
CD137 stimulation. Ifng, in turn, induced macrophage production of other
fibrosis-promoting cytokines and chemokines, including Tnf (191160), Il6
(147620), and Mcp1 (CCL2; 158105). Wang et al. (2010) proposed that
sustained CD137 stimulation is a contributing factor for liver
immunopathology in chronic HBV infection, suggesting that a common
defense pathway against viral infection also causes chronic hepatic
diseases.

MOLECULAR GENETICS

- Variation in Genes Involved in Host Immune Response

By adulthood, 90% of the population in West Africa have been infected
with HBV. Thursz et al. (1997) noted that in most people this is
manifest as an asymptomatic self-limiting infection during childhood,
but approximately 15% of patients develop a persistent infection, and
this often results in chronic liver disease and HCC. Because HBV-induced
HCC is commonly a disease of working-age males in West Africa,
resistance to HBV persistence probably confers some reproductive
advantage. Almarri and Batchelor (1994) found that particular HLA class
II region haplotypes affect the probability that an HBV infection will
become persistent. Thursz et al. (1997) presented evidence supporting
models of overdominant selection in which MHC homozygotes are less
likely to clear an HBV infection and thus more likely to become
persistently infected. In tests of 632 Gambian subjects of whom 223 had
evidence of persistent infection and 409 had successfully cleared the
virus, they found no differences in the class I loci; however,
significantly fewer subjects with persistent infection were heterozygous
for haplotypes of the HLA class II region genes, HLA-DR (see 142860) and
HLA-DQ (see 146880).

To investigate whether TNF (191160) promoter polymorphisms are
associated with clearance of HBV infection, Kim et al. (2003) genotyped
1,400 Korean subjects, 1,109 of whom were chronic HBV carriers and 291
who spontaneously recovered. The TNF promoter alleles that were
previously reported to be associated with higher plasma levels (presence
of -308A or the absence of -863A alleles), were strongly associated with
the resolution of HBV infection. Haplotype analysis revealed that TNF
haplotype 1 (-1031T; -863C; -857C; -308G; -238G; -163G) and haplotype 2
(-1031C; -863A; -857C; -308G; -238G; -163G) were significantly
associated with HBV clearance, showing protective antibody production
and persistent HBV infection, respectively (P = 0.003-0.02).

Thio et al. (2005) genotyped 2 promoter SNPs and 3 exon 1 SNPs in the
MBL2 gene (154545) in a large cohort of individuals with either HBV
persistence or recovery. They found that a promoter SNP, -221G-C, which
leads to deficient MBL production, was more common in subjects with HBV
persistence. Individuals homozygous for the combination of promoter and
exon 1 genotypes associated with the highest amount of functional MBL
had highly increased odds of recovery from infection. In contrast, those
homozygous for the combination of promoter and exon 1 genotypes
associated with the lowest amount of functional MBL were more likely to
have viral persistence.

Thio et al. (2004) genotyped 6 SNPs in CTLA4 (123890) in a large cohort
of individuals with either HBV clearance or persistence. They found that
the wildtype haplotype, which contains -1722T and +49A, was associated
with viral persistence. In contrast, haplotypes containing +49G either
alone or with -1722C were associated with viral clearance. The
association with viral clearance was stronger for individuals homozygous
for +49G. Thio et al. (2004) concluded that genes important in immune
system couterregulation are also important in recovery from chronic
viral illness.

By microsatellite analysis of Gambian families, Frodsham et al. (2006)
identified a class II cytokine receptor gene cluster on chromosome 21q22
as a major susceptibility locus for HBV persistence. They found that
coding SNPs in 2 genes within this cluster, phe8 to ser (F8S;
602376.0001) in IFNAR2 and lys47 to glu (K47E; 123889.0001) in IL10RB
(123889), were associated, both independently and as a haplotype, with a
higher risk of HBV persistence. In both cases, the more common variant
(F8 and K47, respectively) was associated with HBV persistence.

Thio et al. (2008) stated that 95% of adults recover from acute HBV
infection and that the likelihood of recovery is enhanced in those
carrying a 32-bp deletion (601373.0001) in the CCR5 gene (601373), which
results in a nonfunctional receptor. By comparing 181 individuals with
persistent HBV infection with 316 who had recovered, Thio et al. (2008)
showed that the combination of the 32-bp deletion in CCR5 with the minor
allele of a functional promoter polymorphism in the CCR5 ligand, CCL5
(187011), -403G-A, was significantly associated with recovery (odds
ratio = 0.36; P = 0.02). CCL5 -403A without the 32-bp deletion in CCR5
was not associated with HBV recovery, and the 32-bp deletion in CCR5
without CCL5 -403A showed only weak, nonsignificant protection. Thio et
al. (2008) noted that -403A is associated with higher levels of CCL5 in
cell lines. They proposed that excess CCL5 due to -403A combined with
the nonfunctional CCR5 receptor due to the 32-bp deletion favors
recovery from HBV infection. However, Thio et al. (2008) stated that
they could not totally eliminate the possibility that interaction with
the 32-bp deletion in CCR5 is due to another CCL5 SNP, 524T-C, rather
than -403A, because 524C is in tight linkage disequilibrium with -403A.

Kamatani et al. (2009) performed a 2-stage genomewide association study
using 786 Japanese chronic hepatitis B cases and 2,201 controls, and
identified a significant association of chronic hepatitis B with 11 SNPs
in a region including HLA-DPA1 (142880) and HLA-DPB1 (142858). Kamatani
et al. (2009) validated these associations by genotyping 2 SNPs from the
region in 3 additional Japanese and Thai cohorts consisting of 1,300
cases and 2,100 controls (combined P = 6.34 x 10(-39) and 2.31 x
10(-38), odds ratio = 0.57 and 0.56, respectively). Subsequent analyses
revealed risk haplotypes (HLA-DPA1*0202-DPB1*0501 and
HLA-DPA1*0202-DPB1*0301, odds ratio = 1.45 and 2.31, respectively) and
protective haplotypes (HLA-DPA1*0103-DPB1*0402 and
HLA-DPA1*0103-DPB1*0401, odds ratio = 0.52 and 0.57, respectively).
Kamatani et al. (2009) concluded that genetic variants in the HLA-DP
locus are strongly associated with risk of persistent infection with
hepatitis B virus in Asians.

Zhou et al. (2009) investigated SNPs in the IFNGR1 gene (107470) and
their associations with susceptibility to HBV in a Chinese population.
Using PCR and RFLP analysis, they identified 7 SNPs in the IFNGR1 gene.
Comparison of 361 chronic hepatitis B patients, 256 individuals who
spontaneously recovered from HBV infection, and 366 healthy controls
showed that the -56C and -56T alleles of a promoter polymorphism
(107470.0012) were associated with viral clearance and viral
persistence, respectively (P = 0.014). Luciferase reporter analysis
showed that the -56C variant exhibited a higher transcription level than
the -56T variant in a liver cell line. Zhou et al. (2009) concluded that
the -56C/T SNP in the IFNGR1 promoter is associated with the clinical
outcome of HBV infection in Chinese adults.

*FIELD* RF
1. Almarri, A.; Batchelor, J. R.: HLA and hepatitis B infection. Lancet 344:
1194-1195, 1994.

2. Bouchard, M. J.; Wang, L.-H.; Schneider, R. J.: Calcium signaling
by HBx protein in hepatitis B virus DNA replication. Science 294:
2376-2378, 2001.

3. Frodsham, A. J.; Zhang, L.; Dumpis, U.; Taib, N. A. M.; Best, S.;
Durham, A.; Hennig, B. J. W.; Hellier, S.; Knapp, S.; Wright, M.;
Chiaramonte, M.; Bell, J. I.; Graves, M.; Whittle, H. C.; Thomas,
H. C.; Thursz, M. R.; Hill, A. V. S.: Class II cytokine receptor
gene cluster is a major locus for hepatitis B persistence. Proc.
Nat. Acad. Sci. 103: 9148-9153, 2006.

4. Ganem, D.: The X files--one step closer to closure. Science 294:
2299-2300, 2001.

5. Kamatani, Y.; Wattanapokayakit, S.; Ochi, H.; Kawaguchi, T.; Takahashi,
A.; Hosono, N.; Kubo, M.; Tsunoda, T.; Kamatani, N.; Kumada, H.; Puseenam,
A.; Sura, T.; Daigo, Y.; Chayama, K.; Chantratita, W.; Nakamura, Y.;
Matsuda, K.: A genome-wide association study identifies variants
in the HLA-DP locus associated with chronic hepatitis B in Asians. Nature
Genet. 41: 591-595, 2009.

6. Kim, Y. J.; Lee, H.-S.; Yoon, J.-H.; Kim, C. Y.; Park, M. H.; Kim,
L. H.; Park, B. L.; Shin, H. D.: Association of TNF-alpha promoter
polymorphisms with the clearance of hepatitis B virus infection. Hum.
Molec. Genet. 12: 2541-2546, 2003.

7. Seeff, L. B.; Hoofnagle, J. H.: Epidemiology of hepatocellular
carcinoma in areas of low hepatitis B and hepatitis C endemicity. Oncogene 25:
3771-3777, 2006.

8. Shepard, C. W.; Simard, E. P.; Finelli, L.; Fiore, A. E.; Bell,
B. P.: Hepatitis B infection: epidemiology and vaccination. Epidemiol.
Rev. 28: 112-125, 2006.

9. Thio, C. L.; Astemborski, J.; Thomas, R.; Mosbruger, T.; Witt,
M. D.; Goedert, J. J.; Hoots, K.; Winkler, C.; Thomas, D. L.; Carrington,
M.: Interaction between RANTES promoter variant and CCR5-delta-32
favors recovery from hepatitis B. J. Immun. 181: 7944-7947, 2008.

10. Thio, C. L.; Mosbruger, T.; Astemborski, J.; Greer, S.; Kirk,
G. D.; O'Brien, S. J.; Thomas, D. L.: Mannose binding lectin genotypes
influence recovery from hepatitis B virus infection. J. Virol. 79:
9192-9196, 2005.

11. Thio, C. L.; Mosbruger, T. L.; Kaslow, R. A.; Karp, C. L.; Strathdee,
S. A.; Vlahov, D.; O'Brien, S. J.; Astemborski, J.; Thomas, D. L.
: Cytotoxic T-lymphocyte antigen 4 gene and recovery from hepatitis
B virus infection. J. Virol. 78: 11258-11262, 2004.

12. Thursz, M. R.; Thomas, H. C.; Greenwood, B. M.; Hill, A. V. S.
: Heterozygote advantage for HLA class-II type in hepatitis B virus
infection. (Letter) Nature Genet. 17: 11-12, 1997. Note: Erratum:
Nature Genet. 18: 88 only, 1998.

13. Wang, J.; Zhao, W.; Cheng, L.; Guo, M.; Li, D.; Li, X.; Tan, Y.;
Ma, S.; Li, S.; Yang, Y.; Chen, L.; Wang, S.: CD137-mediated pathogenesis
from chronic hepatitis to hepatocellular carcinoma in hepatitis B
virus-transgenic mice. J. Immun. 185: 7654-7662, 2010.

14. Zhou, J.; Chen, D.-Q.; Poon, V. K. M.; Zeng, Y.; Ng, F.; Lu, L.;
Huang, J.-D.; Yuen, K.-Y.; Zheng, B.-J.: A regulatory polymorphism
in interferon-gamma receptor 1 promoter is associated with the susceptibility
to chronic hepatitis B virus infection. Immunogenetics 61: 423-430,
2009.

*FIELD* CN
Paul J. Converse - updated: 5/1/2012
Paul J. Converse - updated: 3/22/2011
Paul J. Converse - updated: 12/10/2009
Ada Hamosh - updated: 10/2/2009
Paul J. Converse - updated: 11/3/2006
Paul J. Converse - updated: 11/1/2006
Paul J. Converse - updated: 9/22/2006

*FIELD* CD
Matthew B. Gross: 9/22/2006

*FIELD* ED
terry: 12/20/2012
mgross: 5/3/2012
terry: 5/1/2012
mgross: 3/22/2011
mgross: 12/11/2009
terry: 12/10/2009
alopez: 10/7/2009
terry: 10/2/2009
mgross: 11/3/2006
mgross: 11/1/2006
mgross: 9/22/2006

MIM 611162
*RECORD*
*FIELD* NO
611162
*FIELD* TI
#611162 MALARIA, SUSCEPTIBILITY TO
MALARIA, RESISTANCE TO, INCLUDED;;
MALARIA, SEVERE, SUSCEPTIBILITY TO, INCLUDED;;
read moreMALARIA, SEVERE, RESISTANCE TO, INCLUDED;;
MALARIA, CEREBRAL, SUSCEPTIBILITY TO, INCLUDED;;
MALARIA, CEREBRAL, RESISTANCE TO, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because variation in several
different genes influences susceptibility and resistance to malaria, as
well as disease progression and severity. These genes include HBB
(141900), ICAM1 (147840), CD36 (173510), CR1 (120620), GYPA (111300),
GYPB (111740), GYPC (110750), TNF (191160), NOS2A (163730), TIRAP
(606252), FCGR2B (604590), and CISH (602441). In addition, a locus
associated with Plasmodium falciparum blood infection level has been
mapped to chromosome 5q31-q33 (PFBI; 248310), a locus for susceptibility
to mild malaria has been mapped to chromosome 6p21.3 (MALS; 609148), a
locus associated with malaria fever episodes has been mapped to
chromosome 10p15 (PFFE1; 611384), and a locus for susceptibility to
placental malarial infection has been mapped to chromosome 6 (FUT9;
606865). Complete protection from Plasmodium vivax infection is
associated with the Duffy blood group-negative phenotype (see 110700).
Alpha(+)-thalassemia (141800), the X-linked disorder G6PD deficiency
(300908), and Southeast Asian ovalocytosis (109270) are associated with
resistance to malaria.

DESCRIPTION

Malaria, a major cause of child mortality worldwide, is caused by
mosquito-borne hematoprotozoan parasites of the genus Plasmodium. Of the
4 species that infect humans, P. falciparum causes the most severe forms
of malaria and is the major cause of death and disease. Although less
fatal, P. malariae, P. ovale, and, in particular, P. vivax infections
are major causes of morbidity. The parasite cycle involves a first stage
in liver cells and a subsequent stage at erythrocytes, when malaria
symptoms occur. A wide spectrum of phenotypes are observed, from
asymptomatic infection to mild disease, including fever and mild anemia,
to severe disease, including cerebral malaria, profound anemia, and
respiratory distress. Genetic factors influence the response to
infection, as well as disease progression and severity. Malaria is the
strongest known selective pressure in the recent history of the human
genome, and it is the evolutionary driving force behind sickle-cell
disease (603903), thalassemia (see 141800), glucose-6-phosphatase
deficiency (300908), and other erythrocyte defects that together
constitute the most common mendelian diseases of humans (Kwiatkowski,
2005; Campino et al., 2006).

PATHOGENESIS

Compared with other microorganisms, P. falciparum malaria parasites
reach very high densities in blood. P. falciparum-infected erythrocytes
(PfIRBCs) induce ICAM1 (147840) expression on human brain microvascular
endothelial cells (HBMECs), but not on human umbilical vein endothelial
cells. PfIRBCs compromise the electrical function of brain endothelium
independently of PfIRBC binding phenotype, suggesting a role for soluble
parasite factors. By performing genomewide transcriptional profiling of
HBMECs after exposure to isogenic PfIRBCs, followed by ELISA for protein
identification, Tripathi et al. (2009) identified upregulated molecules
involved in immune response, apoptosis and antiapoptosis, inflammatory
response, cell-cell signaling, and signal transduction and activation of
the NF-kappa-B (see 164011) cascade. Proinflammatory molecules,
including CCL20 (601960), CXCL1 (155730), CXCL2 (139110), IL6 (147620),
and IL8 (146930), were upregulated more than 100-fold. Tripathi et al.
(2009) concluded that PfIRBC exposure to HBMECs results in a
predominantly proinflammatory response mediated by NF-kappa-B
activation.

By incubating erythrocytes with increasing amounts of anti-CR1
antibodies or soluble CR1 (120620), followed by immunoprecipitation
analysis, Tham et al. (2010) showed that the P. falciparum merozoite
ligand PfRh4 bound to CR1. Levels of PfRh4 binding correlated with CR1
expression on the erythrocyte surface, which is controlled by the CR1
exon 22 SNP (120620.0001). Binding was reduced in individuals homozygous
for low CR1 expression. Parasite invasion of neuraminidase-treated
erythrocytes was also reduced. Tham et al. (2010) concluded that CR1 is
an erythrocyte receptor used by P. falciparum PfRh4 for sialic
acid-independent invasion.

By systematic screening of a library of erythrocyte proteins, Crosnier
et al. (2011) identified basigin (BSG; 109480) as a receptor for PfRh5,
a P. falciparum ligand essential for blood stage growth of the parasite.
Soluble basigin or basigin knockdown inhibited erythrocyte invasion by
all P. falciparum strains, and complete blocking was achieved by
anti-basigin antibodies. OK(a-) red blood cells, which express the
glu92-to-lys (E92K; 109480.0001) variant of basigin, had reduced binding
to PfRh5 due to slower association and faster dissociation rates.
Another basigin variant, leu90 to pro (L90P), did not interact with
PfRh5 at all. Crosnier et al. (2011) concluded that the dependence on a
single receptor-ligand pair across many P. falciparum strains may
provide novel possibilities for therapeutic intervention.

By screening an array of full-length plasma membrane proteins expressed
on human embryonic kidney cells, Turner et al. (2013) identified the
endothelial protein C receptor (EPCR; 600646) as a binding partner of
domain cassette-8 of the Plasmodium falciparum erythrocyte membrane
protein-1 (DC8-PfEMP1). They mapped the PfEMP1 EPCR-binding domain by
ELISA with DC8-PfEMP1C8 variants. Further analysis confirmed that PfEmp1
proteins have diverged into CD36 (173510)- and EPCR-binding subtypes.
DC8-PfEMP1-expressing and parasitized erythrocytes bound to brain
endothelial cells and were inhibited by recombinant EPCR or anti-EPCR
antibodies. Turner et al. (2013) proposed that PfEMP1-EPCR-mediated
cytoadhesion is the major virulence phenotype for severe malaria.

Cserti-Gazdewich et al. (2012) conducted a prospective analysis of ABO
blood groups (see 110300) and cytoadhesion receptors CD36 and ICAM1 in
approximately 2,000 Ugandan children with either uncomplicated or severe
malaria, including cerebral malaria (CM), severe anemia (SA), and lactic
acidosis (LA). Survival was enhanced in individuals with blood group O
and increased monocyte expression of CD36 and ICAM1. Blood group O was
nearly 50% in 180,000 adult blood donors and in children with
uncomplicated malaria, whereas it was approximately 40% in children with
severe malaria. High case fatality rates in cerebral malaria and lactic
acidosis were associated with high platelet CD36 expression and
thrombocytopenia, whereas severe anemia was characterized by low ICAM1
expression. Logistic regression analysis showed that the odds ratios for
the mitigating effects of blood group O, CD36, and ICAM1 phenotypes were
greater than that of sickle cell hemoglobin. Cserti-Gazdewich et al.
(2012) concluded that selection pressure by P. falciparum continues to
shape the human genome.

MAPPING

Rihet et al. (1998) provided evidence for linkage of the level of blood
infection with Plasmodium falciparum and chromosome region 5q31-q33 (see
248310).

Flori et al. (2003) demonstrated linkage of mild malaria to the MHC
region in an urban population living in an endemic area in Burkina Faso
(see 609148).

Timmann et al. (2007) reported significant association between malaria
fever episodes and a locus on chromosome 10p15 (PFFE1; 611384) in a
rural Ghanaian population.

Fortin et al. (2002) reviewed the mapping of gene effects in malaria,
both in humans and in mice, using population studies and experimental
models of malaria susceptibility.

- Associations Pending Confirmation

In a genomewide association study of patients with severe malaria and
unaffected controls from Ghana, Timmann et al. (2012) identified novel
resistance loci for severe malaria within the ATP2B4 gene (108732) on
chromosome 1q32.1 and near the MARVELD3 gene (614094) on chromosome
16q22.2. Several SNPs within the ATP2B4 gene showed significant
association, with dbSNP rs10900585 within intron 2 showing strongest
association (odds ratio = 0.65; P = 6.1 x 10(-9)). ATP2B4 encodes the
major Ca(2+) pump in erythrocytes, the host cells of the pathogenic
stage of malaria, and Timmann et al. (2012) hypothesized that variants
in ATP2B4 may disturb homeostasis of intraerythrocytic Ca(2+)
concentrations and impact parasite reproduction and maturation. The
associated SNP on chromosome 16q22.2, dbSNP 2334880 (odds ratio = 1.24;
P = 3.9 x 10(-8)), is located 6.4 kb upstream of the MARVELD3 gene. The
MARVELD3 product is part of tight junction structures of epithelial and
vascular endothelial cells, and Timmann et al. (2012) noted that
endothelial adherence is important in the pathology of severe malaria.

MOLECULAR GENETICS

- Variation in HBB and Resistance to Malaria

In a review, Kwiatkowski (2005) noted that 3 coding SNPs in the HBB gene
confer resistance to malaria and have risen to high frequency in
different populations: HbS (141900.0243), HbC (141900.0038), and HbE
(141900.0071). The HbS allele is maintained at a frequency of 10% in
malaria-endemic regions, including sub-Saharan Africa and parts of the
Middle East. HbS homozygotes have sickle-cell disease (603903), a
debilitating and often fatal disorder. The heterozygous state, denoted
HbAS, is not associated with any clinical abnormality and confers a
10-fold increase in protection from life-threatening malaria and lesser
protection against mild malaria. The HbC allele is found in several
parts of West Africa, but is less common than HbS. Homozygotes have
relatively mild hemolytic anemia, and both homozygotes and heterozygotes
are protected against severe malaria, though homozygotes show
substantially greater protection. HbE is common in Southeast Asia.
Homozygotes generally have symptomless anemia, and erythrocytes from HbE
heterozygotes are resistant to invasion by P. falciparum.

Rihet et al. (2004) surveyed 256 individuals (71 parents and 185 sibs)
from 53 families in Burkina Faso over 2 years and found that hemoglobin
C carriers were found to have less frequent malaria attacks than AA
individuals within the same age group (P = 0.01). Analysis of individual
hemoglobin alleles yielded a negative association between Hb C and
malaria attack (P = 0.00013). Analyses that took into account
confounding factors confirmed the negative association of Hb C with
malaria attack (P = 0.0074) and evidenced a negative correlation between
Hb C and parasitemia (P = 0.0009).

Fairhurst et al. (2005) reported a marked effect of hemoglobin C on the
cell-surface properties of P. falciparum-infected erythrocytes involved
in pathogenesis. Relative to parasite-infected normal erythrocytes (Hb
AA), parasitized AC and CC erythrocytes showed reduced adhesion to
endothelial monolayers expressing CD36 (173510) and intercellular
adhesion molecule-1 (ICAM1; 147840). They also showed impaired rosetting
interactions with nonparasitized erythrocytes, and reduced agglutination
in the presence of pooled sera from malaria-immune adults. Abnormal
cell-surface display of the main variable cytoadherence ligand, PfEMP-1
(P. falciparum erythrocyte membrane protein-1), correlated with these
findings. The abnormalities in PfEMP-1 display were associated with
markers of erythrocyte senescence, and were greater in CC than in AC
erythrocytes. Fairhurst et al. (2005) suggested that hemoglobin C might
protect against malaria by reducing PfEMP1-mediated adherence of
parasitized erythrocytes, thereby mitigating the effects of their
sequestration in the microvasculature.

Ayodo et al. (2007) performed an association study combined with
evidence of natural selection. The association study tested 10 putative
resistance variants in 471 severe malaria cases (mean age 2.6 years) and
474 controls (mean age 16.9 years) from the Luo tribe, who live in a
malaria-endemic region of Kenya. The authors replicated associations
with HBB and CD36. In the selection study, Ayodo et al. (2007) assembled
population control samples from the Masai, Kikuyu, and Yoruba ethnic
groups. They found that the same variants are unusually differentiated
between the Luo and Yoruba (also historically exposed to malaria in
Nigeria) and the Masai and Kikuyu tribes (both living in nonendemic
regions of Kenya). Although evidence of association for HBB and CD36 was
only moderate by the association analysis alone, formal combination of
evidence of association with evidence from the selection test yielded
greatly increased significance, up to P = 0.000018 for HBB and P =
0.00043 for CD36. Ayodo et al. (2007) concluded that they empirically
demonstrated the theoretical concept of increasing statistical power by
orders of magnitude to detect disease variants by combining association
analysis with evidence of natural selection.

In a genomewide association study of patients with severe malaria and
unaffected controls from Ghana, Timmann et al. (2012) confirmed the
protective effect of sickle cell trait.

- Thalassemia and Resistance to Malaria

The suggestion that alpha(+)-thalassemia (141800) has achieved a high
frequency in some populations as a result of selection by malaria is
based on a number of epidemiologic studies. In the southwest Pacific
region, there is a striking geographic correlation between the frequency
of alpha(+)-thalassemia and the endemicity of Plasmodium falciparum.
Allen et al. (1997) undertook a prospective case-control study of
children with severe malaria on the north coast of Papua New Guinea,
where malaria transmission is intense and alpha(+)-thalassemia affects
more than 90% of the population (homozygotes comprise approximately 55%
and heterozygotes 37% of the population). Compared with normal children,
the risk of having severe malaria was 0.40 in alpha(+)-thalassemia
homozygotes and 0.66 in heterozygotes. Unexpectedly, the risk of
hospital admission with infections other than malaria also was reduced
to a similar degree in homozygotes (0.36) and heterozygotes (0.63). This
clinical study demonstrated that a malaria resistance gene protects
against disease caused by infections other than malaria. A reduction in
mortality greater than that attributable directly to malaria had been
observed after the prevention of malaria by insecticides,
chemoprophylaxis, and insecticide-impregnated bed nets. Previous
observations that direct malaria mortality cannot account for observed
hemoglobin S gene frequencies suggest that the findings of this study
may apply equally to other malaria resistance genes.

In a study of the epidemiology of childhood malaria on the southwestern
Pacific island of Espiritu Santo in Vanuatu, Williams et al. (1996)
found that, paradoxically, both the incidence of uncomplicated malaria
and the prevalence of splenomegaly, an index of malarial infection, were
significantly higher in young children with alpha(+)-thalassemia than in
normal children. Furthermore, this effect was most marked in the
youngest children and for the nonlethal parasite Plasmodium vivax. The
authors speculated that the alpha(+)-thalassemias may have been selected
for the ability to increase susceptibility to P. vivax, which, by acting
as a natural vaccine in this community, induced limited cross-species
protection against subsequent severe P. falciparum malaria.

- Variation in FY and Resistance to P. Vivax Infection

The Duffy-null phenotype (see 110700), which results from a promoter SNP
in the DARC gene (613665.0002), provides complete protection against P.
vivax infection (Kwiatkowski, 2005).

- G6PD Deficiency and Resistance to Malaria

Among Nigerian children with convulsions and heavy parasitemia from
falciparum malaria, Martin et al. (1979) noted a reduced frequency of
G6PD deficiency (305900), an X-linked disorder. They pointed out that
the only support for a role of malaria in selecting for deficiency genes
had been geographic association. The mechanism of protection of
G6PD-deficient cells against falciparum malaria was worked out by
Friedman and Trager (1981). G6PD is critical to the regeneration of
NADPH, a coenzyme that is essential for protection against and repair of
oxidative damage. Red cells deficient in G6PD are more sensitive to
hydrogen peroxide generated by the malaria parasite. The loss of
potassium from the cell and from the parasite is largely responsible for
the death of the parasite. The fava bean contains a variety of
substances that increase the red cells' sensitivity to oxidants. Eating
fava beans and perhaps other foods as yet not identified would be
expected to increase the level of protection against malaria in people
who are heterozygous for G6PD deficiency and for thalassemia. Fetal red
cells likewise have an increased sensitivity to oxidants and a resulting
resistance to malaria. This is true of adult cells that have unusually
high concentration of fetal hemoglobin. Roth et al. (1983) found that
G6PD-deficient red cells of Sardinian hemizygotes and heterozygotes
supported growth of the Plasmodium falciparum parasite in vitro only
about one-third as well as normal red cells. No abnormality of growth
could be demonstrated in red cells from Sardinians with the
beta-zero-thalassemia trait. The authors suggested that the data support
a selective advantage of G6PD deficiency in malarious areas; the
advantage of the female heterozygote may be particularly strong if
resistance to malaria equals that in the hemizygous male, without the
risk of fatal hemolysis.

That resistance to severe malaria is the basis of the high frequency of
G6PD deficiency and that both hemizygotes and heterozygotes enjoy an
advantage was established by Ruwando et al. (1995) in 2 large
case-control studies of more than 2,000 African children. They found
that the common African form of G6PD deficiency (G6PD A-; 305900.0002)
was associated with a 46 to 58% reduction in risk of severe malaria for
both female heterozygotes and male hemizygotes. A mathematical model
incorporating the measured selective advantage against malaria suggested
that a counterbalancing selective disadvantage, associated with this
enzyme deficiency, has retarded its rise in frequency in malaria-endemic
regions.

Cappadoro et al. (1998) found that with 5 different strains of
Plasmodium falciparum, there was no significant difference in either
invasion or maturation when the parasites were grown in either normal or
G6PD-deficient (Mediterranean variant; 305900.0006) erythrocytes. With
all of these strains and at different maturation stages, they were
unable to detect any difference in the amount of P. falciparum-specific
G6PD mRNA in normal versus deficient parasitized erythrocytes. By
contrast, in studies of phagocytosis of parasitized erythrocytes by
human adherent monocytes, they found that when the parasites were at the
ring stage, deficient ring-stage parasitized erythrocytes (RPE) were
phagocytized 2.3 times more intensely than normal RPEs, whereas there
was no difference when the parasites were at the more mature trophozoite
stage, i.e., trophozoite-stage parasitized erythrocytes (TPEs). The
level of reduced glutathione was remarkably lower in deficient RPEs
compared with normal RPEs. Cappadoro et al. (1998) concluded that
impaired antioxidant defense in deficient RPEs may be responsible for
membrane damage followed by phagocytosis. Because RPEs, unlike TPEs, are
nontoxic to phagocytes, the increased removal by phagocytosis of RPEs
would reduce maturation to TPEs and to schizonts and may be a highly
efficient mechanism of malaria resistance in deficient subjects.

Louicharoen et al. (2009) investigated the effect of the G6PD-Mahidol
487A variant (305900.0005) on human survival related to P. vivax and P.
falciparum malaria in Southeast Asia. They showed that strong and recent
positive selection has targeted the Mahidol variant over the past 1,500
years. The authors found that the G6PD-Mahidol variant reduces vivax,
but not falciparum, parasite density in humans, which indicates that P.
vivax has been a driving force behind the strong selective advantage
conferred by this mutation.

- Variation in GYPA and Resistance to Malaria

Red cells with the rare En(a-) variant of GYPA (111300) are resistant to
falciparum malaria (Pasvol et al., 1982).

- Variation in GYPB and Resistance to Malaria

Red cells with the rare U(-) variant of GYPB (111740) are relatively
resistant to invasion by P. falciparum (Pasvol and Wilson, 1982).

- Variation in GYPC and Resistance to Malaria

Deletion of exon 3 in the GYPC gene (110750.0002) has been found in
Melanesians; this alteration changes the serologic phenotype of the
Gerbich (Ge) blood group system (110750), resulting in Ge negativity
(Booth and McLoughlin, 1972; Serjeantson et al., 1994). The GYPC exon 3
deletion allele reaches a high frequency (46.5%) in coastal areas of
Papua New Guinea where malaria is hyperendemic (Patel et al., 2001).
Plasmodium falciparum erythrocyte-binding antigen-140 (EBA140, also
known as BAEBL) binds with high affinity to the surface of human
erythrocytes. Maier et al. (2003) showed that the receptor for EBA140 is
glycophorin C and that this interaction mediates a principal P.
falciparum invasion pathway into human erythrocytes. EBA140 does not
bind to GYPC in Ge-negative erythrocytes, nor can P. falciparum invade
such cells using this invasion pathway. This provides compelling
evidence that Ge negativity has arisen in Melanesian populations through
natural selection by severe malaria.

- Southeast Asian Ovalocytosis and Resistance to Cerebral
Malaria

Kidson et al. (1981) found that ovalocytic erythrocytes from Melanesians
were resistant to invasion by malaria parasites. Baer (1988) suggested
that Malaysian elliptocytosis (109270) may be a balanced polymorphism,
i.e., that individuals homozygous for the elliptocytosis allele may be
differentially susceptible to mortality, whereas the heterozygote is at
an advantage. Hadley et al. (1983) showed that Melanesian elliptocytes
were highly resistant to invasion by Plasmodium knowlesi and P.
falciparum in vitro.

The band 3 variant in southeast Asian ovalocytosis (109270.0002) may
prevent cerebral malaria, but it exacerbates malarial anemia and may
also increase acidosis, a major determinant of mortality in malaria.
Allen et al. (1999) undertook a case-control study of children admitted
to hospital in a malarious area of Papua New Guinea. The 24-bp deletion,
detected by PCR, was present in 0 of 68 children with cerebral malaria,
compared with 6 (8.8%) of 68 matched community controls. Median
hemoglobin levels were 1.2 g/dl lower in malaria cases with southeast
Asian ovalocytosis than in controls (P = 0.035), but acidosis was not
affected. The band 3 protein mediates the cytoadherence of parasitized
erythrocytes in vitro. The remarkable protection that the variant
affords against cerebral malaria may offer a valuable approach to a
better understanding of the mechanisms of adherence of parasitized
erythrocytes to vascular endothelium and the pathogenesis of cerebral
malaria.

- Variation in CD36 and Susceptibility or Resistance to Cerebral
Malaria

CD36 is a major receptor for Plasmodium falciparum-infected
erythrocytes. Aitman et al. (2000) found that African populations
contain an exceptionally high frequency of mutations in CD36 (173510).
Unexpectedly, these mutations (173510.0002 and 173510.0003) that cause
CD36 deficiency (608404) were associated with susceptibility to severe
cerebral malaria, suggesting that the presence of distinct CD36
mutations in Africans and Asians is due to some selection pressure other
than malaria.

In 475 adult Thai patients with P. falciparum malaria, Omi et al. (2003)
screened for variation in the CD36 gene and examined possible
association between CD36 polymorphisms and the severity of malaria. They
identified 9 CD36 polymorphisms with a frequency of more than 15% for
the minor allele. Of these, the -14T-C allele in the upstream promoter
region and the -53G-T allele in the downstream promoter region were
significantly decreased in patients with cerebral malaria compared with
those with mild malaria. Linkage disequilibrium (LD) analysis between
the 9 common polymorphisms revealed 2 blocks with strong LD in the CD36
gene; the -14T-C and -53G-T polymorphisms were within the upstream block
of 35 kb from the upstream promoter to exon 8. Another polymorphism,
consisting of 12 TG repeats in intron 3 (173510.0004), was strongly
associated with reduction in the risk of cerebral malaria. Omi et al.
(2003) demonstrated by RT-PCR amplification that this IVS3(TG)12
polymorphism is involved in the nonproduction of the variant CD36
transcript that lacks exons 4 and 5. Because exon 5 of the gene is known
to encode the ligand-binding domain for P. falciparum-infected
erythrocytes, IVS3(TG)12 itself or a primary variant on the haplotype
with IVS3(TG)12 may be responsible for protection from cerebral malaria
in Thailand.

Ayodo et al. (2007) sought to demonstrate that statistical power to
detect disease variants can be increased by weighting candidates by
their evidence of natural selection. Although evidence of association
for HBB and CD36 was only moderate by an association analysis alone,
formal combination of evidence of association with evidence from a
selection test yielded greatly increased significance, up to P =
0.000018 for HBB and P = 0.00043 for CD36.

- Variation in CR1 and Resistance to Malaria

The Knops blood group system (607486) is a system of antigens located on
CR1. Rowe et al. (1997) demonstrated that CR1 is involved in malarial
rosetting, a process associated with cerebral malaria, which is the
major cause of mortality in Plasmodium falciparum malaria. They showed
that rosette formation was considerably reduced with Sl(a-) Knops
phenotype RBCs, indicating that this antigen on CR1 is involved in
rosetting. Because Sl(a-) is more common in persons of African ancestry,
a protective role was suggested (Moulds and Moulds, 2000).

CR1-deficient RBCs show greatly reduced rosetting, leading Cockburn et
al. (2004) to hypothesize that if rosetting is a direct cause of malaria
pathology, CR1-deficient individuals should be protected against severe
disease. They showed that RBC CR1 deficiency occurs in up to 80% of
healthy individuals from the malaria-endemic regions of Papua New
Guinea. This RBC CR1 deficiency is associated with polymorphisms in the
CR1 gene (e.g., 120620.0001) and, unexpectedly, with alpha-thalassemia,
a common genetic disorder in Melanesian populations. Analysis of a
case-control study demonstrated that the CR1 polymorphisms and
alpha-thalassemia independently confer protection against severe
malaria. Thus, Cockburn et al. (2004) identified CR1 as a new malaria
resistance gene and provided compelling evidence that rosetting is an
important parasite virulence phenotype that should be a target for drug
and vaccine development.

- Variation in ICAM1 and Susceptibility to Cerebral Malaria

The malarial parasite Plasmodium falciparum has acted as a potent
selective force on the human genome. The particular virulence of this
organism was thought to be due to the adherence of parasitized red blood
cells to small vessel endothelium through several receptors, including
CD36, thrombospondin (THBS1; 188060), and ICAM1, and parasite isolates
differ in their ability to bind to each. Immunohistochemical studies
implicated ICAM1 as having potential importance in the pathogenesis of
cerebral malaria, leading Fernandez-Reyes et al. (1997) to reason that
if any single receptor were involved in the development of cerebral
malaria, then in view of the high mortality of that complication,
natural selection should have produced variants with reduced binding
capacity. Fernandez-Reyes et al. (1997) amplified and sequenced the
N-terminal immunoglobulin-like domain of the ICAM1 gene from the genomic
DNA of 24 asymptomatic children in Kilifi, Kenya. The only mutation
found was an A-to-T transversion at nucleotide 179, causing a
lys29-to-met substitution (K29M; 147840.0001), which the authors called
'ICAM1 Kilifi.' In studies of the association of the K29M polymorphism
with cerebral malaria, they found, to their surprise, that the
homozygous ICAM1 Kilifi genotype was associated with susceptibility to
cerebral malaria with a relative risk of 2.23, and heterozygotes with a
relative risk of 1.39. The frequency of the K29 allele was 0.668 and the
frequency of the M29 Kilifi allele was 0.332. Fernandez-Reyes et al.
(1997) noted that, while this association strengthened the link between
ICAM1 and cerebral malaria, a mutation that confers susceptibility is
unlikely to have arisen at such high frequency in the absence of some
counteractive selective advantage. These counterintuitive results had
implications for the mechanism of malaria pathogenesis, resistance to
other infectious agents, and transplant immunology. The Kilifi allele
was not identified in 99 unrelated Caucasians or in 40 multigeneration
families from the CEPH collection. Screening of 20 Gambian samples
produced a similar frequency of the Kilifi allele to that seen in Kenya.

Bellamy et al. (1998) found no association between the ICAM1 Kilifi
variant and cerebral malaria in a case-control study of West Africans.

- Variation in Major Histocompatibility Complex Genes and
Resistance to Severe Malaria

By means of a large case-controlled study of malaria in West African
children, Hill et al. (1991) showed that HLA-Bw53 (see HLA-B; 142830)
and the HLA class II haplotype, DRB1*1302/DQB1*0501 (see HLA-DRB1;
142857), were independently associated with protection from severe
malaria. The antigens listed are common in West Africans but rare in
other racial groups. In this population, they account for as great a
reduction in disease incidence as the sickle-cell hemoglobin variant.
Although the relative strength of the protection is less than that of
the sickle-cell variant, the greater frequency of the DQB1 (see
HLA-DQB1; 604305) polymorphism makes the net effect on resistance to
malaria comparable. The findings support the hypothesis that the
extraordinary polymorphism of major histocompatibility complex genes has
evolved primarily through natural selection by infectious pathogens.

Hill et al. (1992) further investigated the protective association
between HLA-B53 and severe malaria by sequencing peptides eluted from
this molecule followed by screening of candidate epitopes from
pre-erythrocytic-stage antigens of Plasmodium falciparum in biochemical
and cellular assays. Among malaria-immune Africans, they found that
HLA-B53-restricted cytotoxic T lymphocytes recognized a conserved
nonamer peptide from liver-stage-specific antigen-1 (LSA-1), but no
HLA-B53-restricted epitopes were identified in other malaria antigens.
The findings of this 'reverse immunogenetic' approach indicated a
possible molecular basis for this HLA-disease association and supported
the candidacy of LSA-1 as a component for a malaria vaccine.

Sjoberg et al. (1992) found that levels of antibody to a major malarial
antigen developing in individuals living in northern Liberia, where
malaria is holoendemic and perennial, were more concordant within
monozygotic twin pairs than in dizygotic pairs or in age- and
sex-matched sibs living under similar environmental conditions. The
results supported the conclusion that the antibody responses were
genetically regulated. No association was found with different HLA class
II alleles and haplotypes, suggesting that the variation in the antibody
response found in this study reflected the impact of factors encoded by
genes outside the HLA class II region.

- Variation in TNF and Susceptibility to Cerebral Malaria

Because fatal cerebral malaria is associated with high circulating
levels of TNFA (TNF; 191160), McGuire et al. (1994) undertook a large
case-control study in Gambian children. The study showed that
homozygotes for the TNF2 allele (-308G-A; 191160.0004), a variant of the
TNFA gene promoter region, had a relative risk of 7 for death or severe
neurologic sequelae due to cerebral malaria. Although the TNF2 allele is
in linkage disequilibrium with several neighboring HLA alleles, McGuire
et al. (1994) showed that this disease association was independent of
HLA class I and class II variation. The data suggested that regulatory
polymorphisms of cytokine genes can affect the outcome of severe
infection. The maintenance of the TNF2 allele at a gene frequency of
0.16 in The Gambia implies that the increased risk of cerebral malaria
in homozygotes is counterbalanced by some biologic advantage.

Through systematic DNA fingerprinting of the TNF promoter region, Knight
et al. (1999) identified a SNP (-376G-A; 191160.0003) that caused the
helix-turn-helix transcription factor OCT1 (POU2F1; 164175) to bind to a
novel region of complex protein-DNA interactions and alter gene
expression in human monocytes. The OCT1-binding genotype, found in
approximately 5% of Africans, was associated with 4-fold increased
susceptibility to cerebral malaria in large studies comparing cases and
controls in West African and East African populations, after correction
for other known TNF polymorphisms and linked HLA alleles.

- Variation in NOS2A and Resistance to Malaria

Kun et al. (1998) examined whether high plasma concentrations of nitric
oxide found in severe malaria were due to variation in the promoter
region of NOS2 (163730). Heterozygosity for a -969G-C SNP (163730.0002)
was present in 30 of 100 Gambian children with mild malaria, but in only
17 of 100 Gambian children with severe malaria. The SNP was not found in
any of 100 Germans. Heterozygous individuals were also at a
significantly lower risk of reinfection.

From studies in Tanzania and Kenya, Hobbs et al. (2002) identified a
novel SNP, -1173C-T (163730.0001), in the NOS2A promoter that was
significantly associated with protection from symptomatic malaria and
severe malarial anemia.

- Variation in TIRAP and Resistance to Malaria

Khor et al. (2007) reported a case-control study of 6,106 individuals
from the U.K., Vietnam, and several African countries with invasive
pneumococcal disease (see 610799), bacteremia, malaria, and tuberculosis
(607948). Genotyping 33 SNPs, they found that heterozygous carriage of a
leucine substitution of ser180 (606252.0001) in TIRAP (606252) was
associated independently with all 4 infectious diseases in the different
study populations. Combining the study groups, they found substantial
support for protective effect of S180L heterozygosity against these
infectious diseases.

- Variation in FCGR2B and Resistance to Malaria

Clatworthy et al. (2007) found an increased frequency of the I232T
polymorphism (604590.0001) of the FCGR2B gene (604590) in Asian and
African populations, broadly corresponding to regions where malaria is
endemic. The systemic lupus erythematosus (SLE; 152700)-associated I232T
polymorphism was associated with enhanced phagocytosis of Plasmodium
falciparum-infected human erythrocytes. Clatworthy et al. (2007)
concluded that FCGR2B is important in controlling the immune response to
malaria parasites and suggested that polymorphisms predisposing to SLE
in Asians and Africans may be maintained because the variants reduce
susceptibility to malaria.

By comparing genotypes of patients with SLE from Hong Kong and the UK
with those of ethnically matched controls, followed by metaanalysis
using with other studies on southeast Asian and Caucasian SLE patients,
Willcocks et al. (2010) found that homozygosity for T232 of the I232T
polymorphism was strongly associated with SLE in both ethnic groups.
When studies in Caucasians and southeast Asians were combined, T232
homozygosity was associated with SLE with an odds ratio of 1.73 (P = 8.0
x 10(-6)). Willcocks et al. (2010) noted that the T232 allele of the SNP
is more common in southeast Asians and Africans, populations where
malaria is endemic, than in Caucasians. Homozygosity for T232 was
significantly associated with protection from severe malaria in Kenyan
children (odds ratio = 0.56; P = 7.1 x 10(-5)), but no association was
found with susceptibility to bacterial infection. Willcocks et al.
(2010) proposed that malaria may have driven retention of a polymorphism
predisposing to a polygenic autoimmune disease and thus may begin to
explain the ethnic differences seen in the frequency of SLE.

- Blood Group O and Resistance to Severe Malaria

Rowe et al. (2007) noted that Plasmodium falciparum-induced rosetting
(i.e., the spontaneous binding of infected erythrocytes to uninfected
erythrocytes) is thought to contribute to the pathogenesis of severe
malaria by obstructing microvascular blood flow. Rosetting is reduced in
blood group O (see 110300) erythrocytes compared with non-O blood
groups, presumably due to group O individuals having disaccharide H
antigens resulting from a lack of the terminal glycosyltransferases
necessary to produce the trisaccharides found with A and B antigens.
Rosettes that do form in group O red cells are smaller and more easily
disrupted than those in group A, B, or AB red cells. Rowe et al. (2007)
confirmed that rosetting was reduced in individuals with blood group O,
intermediate in blood groups A and B, and highest in group AB. A matched
case control study of 567 Malian children found that group O was present
in only 21% of severe malaria cases compared with approximately 44% of
uncomplicated malaria control cases and healthy controls. Rowe et al.
(2007) concluded that group O is associated with a 66% reduction in the
odds of developing severe malaria compared with non-O blood groups, and
they reported preliminary evidence that similar protection is found in
Kenyan children. The authors also proposed that group O does not occur
at higher frequency in some malaria endemic regions due to increased
susceptibility to cholera and other diarrheal diseases, resulting in
balanced polymorphism.

In a genomewide association study of patients with severe malaria and
unaffected controls from Ghana, Timmann et al. (2012) confirmed the
protective effect of blood group O.

- Variation in GNAS and Susceptibility to Severe Malaria

Using metaanalysis combining data from case control and family studies
in Gambia, Kenya, and Malawi and a case control study from Ghana, Auburn
et al. (2008) detected associations between intronic or conservative
SNPs of GNAS (139320) and severe malaria. SNPs with significant
associations clustered in the 5-prime end of GNAS. Auburn et al. (2008)
proposed that the impact of GNAS on malaria parasite invasion efficacy
may alter susceptibility to disease.

- Variation in TIM1 and Resistance to Cerebral Malaria

By screening for polymorphisms of TIM1 (HAVCR1; 606518), TIM3 (HAVCR2;
606652), and TIM4 (TIM4D; 610096) in 478 Thai patients infected with
Plasmodium falciparum, Nuchnoi et al. (2008) identified a statistically
significant association between protection against cerebral malaria and
a TIM1 promoter haplotype consisting of 3 derived alleles, -1637G-A
(dbSNP rs7702919), -1549G-C (dbSNP rs41297577), and -1454G-A (dbSNP
rs41297579). Allele-specific transcription quantification analysis
revealed that TIM1 mRNA levels were higher for the protective promoter
haplotype than for the other promoter haplotype. Nuchnoi et al. (2008)
proposed that engagement of TIM1 and T-cell receptor stimulation may
induce antiinflammatory Th2 cytokine production and protect from
development of cerebral malaria by downregulating inflammatory cytokines
such as TNF (191160) and IFNG (147570).

- Variation in IL12B and Susceptibility to Cerebral Malaria

Using a family-based association study with 240 Malian families, Marquet
et al. (2008) investigated 21 markers in IL12-related genes for
involvement in susceptibility to cerebral malaria (CM). They found that
the IL12B (161561) promoter polymorphism dbSNP rs17860508, in which GC
is replaced with CTCTAA, was associated with susceptibility to CM. The
CTCTAA allele and the GC/CTCTAA heterozygous genotype were associated
with increased risk of CM (P of 0.0002 and 0.00002, respectively).
Children with the GC/CTCTAA genotype had a higher risk of CM than
children homozygous for either allele (odds ratio of 2.11; P less than
0.0001). Among 134 CM children with a heterozygous parent, a significant
number received the CTCTAA allele. Marquet et al. (2008) noted that
heterozygosity for dbSNP rs17860508 is associated with reduced IL12B
expression and reduced IL12 secretion, and that low IL12 and IFNG
(147570) levels are associated with CM. They proposed that Th1 responses
may reduce the parasite load and severe malaria risk.

- Variation in FUT9 and Susceptibility to Placental Malaria
Infection

Sikora et al. (2009) carried out a nested case-control study on 180
Mozambican pregnant women with placental malaria infection and 180
controls within an intervention trial of malaria prevention. Subjects
were genotyped at 880 SNPs in a set of 64 functionally related genes
involved in glycosylation and innate immunity. A T-C SNP (dbSNP
rs3811070) located in the 5-prime untranslated region (UTR) of the FUT9
gene (606865) on chromosome 6q16 was significantly associated with
placental malaria infection (odds ratio, 2.31; corrected p = 0.038).
Haplotype analysis revealed a similarly strong association for a common
4-SNP TTCA haplotype including dbSNP rs3811070. The TTCA haplotype spans
40 kb in the 5-prime UTR and contains the second exon of FUT9. The FUT9
gene encodes a fucosyltransferase that catalyzes the last step in the
biosynthesis of the Lewis-x antigen, which forms part of the Lewis blood
group-related antigens. Sikora et al. (2009) suggested an involvement of
this antigen in the pathogenesis of placental malaria infection.

- Variation in FCGR2A and Susceptibility to Severe Malaria

The his131-to-arg (H131R; 146790.0001) polymorphism in the extracellular
domain of FCGR2A reduces the receptor's affinity for IgG2 and IgG3
isotypes (see 147100) but increases its binding of C-reactive protein
(CRP; 123260). By studying 2,504 Ghanaian children with severe malaria
and 2,027 healthy matched controls, Schuldt et al. (2010) found that
homozygosity for 131R was positively associated with severe malaria
(odds ratio = 1.20; p = 0.007; p corrected for multiple testing =
0.021), and, after stratification for phenotypes, with severe anemia
(odds ratio = 1.33; p = 0.001; p corrected = 0.009), but not with
cerebral malaria or other malaria complications or with parasitemia
levels. Schuldt et al. (2010) concluded that the CRP-binding variant of
FCGR2A is associated with malarial anemia, suggesting a role for CRP
defense mechanisms in pathogenesis of this condition.

- Resistance Versus Tolerance

Hosts can in principle employ 2 different strategies to defend
themselves against parasites: resistance and tolerance. Animals
typically exhibit considerable genetic variation for resistance. Using
rodent malaria in laboratory mice as a model system and the statistical
framework developed by plant pathogen biologists, Raberg et al. (2007)
demonstrated genetic variation for tolerance, as measured by the extent
to which anemia and weight loss increased with increasing parasite
burden. Moreover, resistance and tolerance were negatively genetically
correlated. Raberg et al. (2007) concluded that their results mean that
animals, like plants, can evolve 2 conceptually different types of
defense, a finding that has important implications for the understanding
of the epidemiology and evolution of infectious diseases.

- Reviews

Nagel and Roth (1989) reviewed genetic disorders of the red cell,
including abnormal hemoglobins, G6PD deficiency, and absence of Duffy
blood group antigen, that influence resistance against malaria infection
in humans.

Kwiatkowski (2005) provided an overview of genetic resistance to
malaria.

Campino et al. (2006) reviewed mendelian and complex genetics of
susceptibility and resistance to parasitic infections, including
malaria.

ANIMAL MODEL

Ferreira et al. (2011) demonstrated that wildtype mice or mice
expressing normal human Hb, but not mice expressing sickle human Hb
(Hbs; 141900.0243), developed experimental cerebral malaria (ECM) 6 to
12 days after infection with the murine malaria parasite, Plasmodium
berghei. The Hbs mice eventually succumbed to the unrelated condition of
hyperparasitemia-induced anemia. Tolerance to Plasmodium infection was
associated with high levels of Hmox1 (141250) expression in
hematopoietic cells, and mice expressing Hbs became susceptible to ECM
when Hmox1 expression was inhibited. Hbs induced expression of Hmox1 in
an Nrf2 (NFE2L2; 600492)-dependent manner, which inhibited the
production of chemokines and Cd8-positive T cells associated with ECM
pathogenesis. Ferreira et al. (2011) concluded that sickle hemoglobin
suppresses the onset of ECM via induction of HMOX1 and the production of
carbon monoxide, which inhibits the accumulation of free heme, affording
tolerance to Plasmodium infection.

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*FIELD* CN
Paul J. Converse - updated: 12/9/2013
Paul J. Converse - updated: 8/22/2013
Paul J. Converse - updated: 7/29/2013
Paul J. Converse - updated: 9/26/2012
Paul J. Converse - updated: 6/19/2012
Paul J. Converse - updated: 1/18/2012
Paul J. Converse - updated: 11/11/2011
Paul J. Converse - updated: 5/5/2011
Paul J. Converse - updated: 4/29/2011
George E. Tiller - updated: 6/28/2010
Ada Hamosh - updated: 1/6/2010
Paul J. Converse - updated: 11/24/2009
Paul J. Converse - updated: 11/2/2009
Paul J. Converse - updated: 1/26/2009
Paul J. Converse - updated: 1/8/2009
Paul J. Converse - updated: 8/21/2008
Ada Hamosh - updated: 11/21/2007
Paul J. Converse - updated: 7/17/2007
George E. Tiller - updated: 7/6/2007
Paul J. Converse - updated: 7/5/2007

*FIELD* CD
Matthew B. Gross: 7/2/2007

*FIELD* ED
mgross: 01/06/2014
mcolton: 12/9/2013
mgross: 10/25/2013
carol: 10/24/2013
mgross: 8/22/2013
alopez: 8/7/2013
alopez: 7/29/2013
mgross: 9/27/2012
terry: 9/26/2012
terry: 7/3/2012
mgross: 6/19/2012
mgross: 1/18/2012
mgross: 11/17/2011
terry: 11/11/2011
terry: 5/20/2011
mgross: 5/11/2011
terry: 5/5/2011
mgross: 5/3/2011
terry: 4/29/2011
mgross: 12/21/2010
wwang: 7/21/2010
terry: 6/28/2010
alopez: 6/10/2010
alopez: 1/19/2010
terry: 1/6/2010
alopez: 11/24/2009
mgross: 11/2/2009
wwang: 8/24/2009
terry: 4/8/2009
carol: 3/31/2009
mgross: 1/26/2009
mgross: 1/8/2009
mgross: 8/21/2008
terry: 8/21/2008
mgross: 4/1/2008
alopez: 11/28/2007
terry: 11/21/2007
mgross: 8/27/2007
terry: 7/17/2007
mgross: 7/9/2007
wwang: 7/6/2007
mgross: 7/5/2007