Summary
Insulin-dependent diabetes mellitus (IDDM) is associated with class II molecules of the MHC on chromosome 6, in particular HLA-DR and -DQ al-leles, but a pathogenic role for TNF-a in the class III region of the MHC has also been implied. We therefore tested whether there was any independent association between a biallelic TNF polymorphism and IDDM. The TNF2 allele was present in 61 of 114 (54 %) IDDM patients compared to 101 of 253 (40 %) control subjects (odds ratio 1.73; p > 0.02). Stratification analysis in individuals matched for HLA-DR3 revealed, however, that this association was not independent of HLA-DR3 and is most likely to be a result of linkage disequilibrium between these alleles.
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Abbreviations
- IDDM:
-
insulin-dependent diabetes mellitus
- TNF-a:
-
tumour necrosis factor alpha
- PCR:
-
polymerase chain reaction
- SSCP:
-
single stranded conformation polymorphism
References
Todd JA (1990) Genetic control of autoimmunity in IDDM. Immunology Today 11: 122–129
Wolf E, Spencer KM, Cudworth AG (1983) The genetic susceptibility to type 1 (insulin-dependent) diabetes: analysis of the HLA-DR association. Diabetologia 24: 224–230
Rotter JI, Anderson CE, Rubin R, Congleton JE, Terasaki PI, Rimoin DL (1983) HLA genotypic study of insulin-dependent diabetes; the excess of DR3/DR4 heterozygotes allows rejection of the recessive hypothesis. Diabetes 32: 169–174
Todd JA, Bell JI, McDevitt HO (1987) HLA-DQβgene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature 329: 599–604
Horn GT, BugawanTL, Long C, Erlich HA (1988) Allelic sequence variation of the HLA-DQ loci: relationship to sero-logy and insulin-dependent diabetes susceptibility. Proc Natl Acad Sci USA 85: 6012–6016
Yamagata K, Nakajima H, Hanafusa T et al. (1989) Aspartic acid at position 57 of DQβ chain does not protect against type 1 (insulin-dependent) diabetes mellitus in Japanese subjects. Diabetologia 32: 762–764
Awata T, Kuzuya T, Matsuda A (1990) High frequency of aspartic acid at position 57 of HLA-DQ beta chain in Japanese IDDM patients and non-diabetic subjects. Diabetes 39: 266–269
Cavan DA, Jacobs KH, Penny MA et al. (1993) Both DQA1 and DQB1 genes are implicated in HLA-associated protection from type 1 (insulin-dependent) diabetes mellitus in a British Caucasian population. Diabetologia 36: 252–257
Todd JA, Mijovic C, Fletcher J, Jenkins D, Bradwell AR, Barnett AH (1989) Identification of susceptibility loci for insulin-dependent diabetes mellitus by trans-racial gene mapping. Nature 338: 587–589
Erlich HA, Zeidler A, Chang J et al. (1993) HLA class II al-leles and susceptibility and resistance to insulin-dependent diabetes mellitus in Mexican-American families. Nature Genetics 3: 358–364
Dawkins RL, Martin E, Saueracker G, Kay PH, Leaver A, Christiansen FT (1990) Supratypes and ancestral haplotypes in IDDM: potential importance of central non-HLA MHC genes. J Autoimmunity 3: 63–68
Christiansen FT, Saueracker GC, Leaver AL, Tokunaga K, Cameron PU, Dawkins RL (1990) Characterization of MHC ancestral haplotypes associated with insulin-dependent diabetes mellitus: evidence for involvement of non-HLA genes. J Immunogenetics 17: 379–386
Degli-Esposti MA, Abraham LJ, McCann V, Spies T, Christiansen FT, Dawkins RL (1992) Ancestral haplotypes reveal the role of the central MHC in the immunogenetics of IDDM. Immunogenetics 36: 345–356
Spies T, Morton CC, Nedospasov SA, Fiers W, Pious D, Strominger JL (1986) Genes for the tumor necrosis factors alpha and beta are linked to the human major histocompati-bility complex. Proc Natl Acad Sci USA 83: 8699–8702
Nedwin GE, Naylor SL, Sakaguchi AY et al. (1985) Human lymphotoxin and tumor necrosis factor genes: structure, ho-mology and chromosomal localization. Nucleic Acids Res 13: 6361–6373
Bendtzen K, Buschard K, Diamant M, Horn T, Svenson M, the Thyroid Cell Group (1989) Possible role of IL-1, TNF-alpha, and IL-6 in insulin-dependent diabetes mellitus and autoimmune thyroid disease. Lymphokine Res 8: 335–340
Campbell IL, Harrison LC (1990) Molecular pathology of IDDM. Mol Biol Med 7: 299–309
Wilson AG, di Giovine FS, Blakemore AIF, Duff GW (1992) Single base polymorphism in the human tumour necrosis factor alpha (TNFα) gene detectable by Ncol restriction of PCR product. Hum Mol Gen 1: 353
Wilson AG, de Vries N, Pociot F, di Giovine FS, van der Putte LBA, Duff GW (1993) An allelic polymorphism within the human tumor necrosis factor a promoter region is strongly associated with HLA Al, B8 and DR3 alleles. J Exp Med 177: 557–560
WHO Study Group (1985) Diabetes mellitus. World Health Organization Technical Reports Series 727, Geneva, p 11
Higuchi R (1989) PCR technology. Stockton Press, New York
Vaughan RW, Lanchbury JSS, Marsh SGE, Hall MA, Bod-mer JG, Welsh KI (1990) The application of oligonucleotide probes to HLA class II typing of the DRB sub-region. Tissue Antigens 36: 149–155
Vaughan RW (1991) PCR-SSO typing for HLA-DRB alleles. Eur J Immunogenetics 18: 33–44
Haldane JBS (1955) The estimation and significance of the logarithm of a ratio of frequencies. Ann Hum Genet 20: 309–311
Pociot F, Wilson AG, Nerup J, Duff GW (1993) No independent association between a TNF-a promoter region polymorphism and insulin-dependent diabetes mellitus (IDDM). Eur J Immunol 23: 3050–3053
Jacob CO, Fronek Z, Lewis GD, Koo M, Hansen JA, McDevitt HO (1990) Heritable major histocompatibility complex class II-associated differences in production of tumour necrosis factor a: relevance to genetic predisposition to systemic lupus erythematosus. Proc Natl Acad Sci USA 87: 1233–1237
Pociot F, Briant L, Jongeneel CV et al. (1993) Association of tumor necrosis factor (TNF) and class II major histocompatibility complex mononuclear cells: a possible link to insulin-dependent diabetes mellitus. Eur J Immunol 23: 224–231
Abraham LJ, French MAH, Dawkins RL (1993) Polymorphic MHC ancestral haplotypes affect the activity of tumour necrosis factor-alpha. Clin Exp Immunol 92: 14–18
Messer G, Spengler U, Jung MC et al. (1991) Polymorphic structure of the tumor necrosis factor (TNF) locus: an Ncol polymorphism in the first intron of the TNF-beta gene correlates with a variant amino acid in position and a reduced level of TNF-beta production. J Exp Med 173: 209–219
Webb GC, Chaplin DD (1990) Genetic variability at the human tumor necrosis factor loci. J Immunol 145: 1278–1285
Jongoneel CV, Briant L, Udalova I A, Seven A, Nedospasov SA, Cambon-Thomsen A (1991) Extensive genetic polymorphism in the human tumor necrosis factor region and relation to extended HLA haplotypes. Proc Natl Acad Sci USA 88: 9717–9721
Nedospasov SA, Udalova IA, Kuprash DV, Turetskaya RL (1991) DNA sequence polymorphism at the human tumor necrosis factor (TNF) locus. Numerous TNF/lymphotoxin alleles tagged by two closely linked microsatellites in the upstream region of the lymphotoxin (TNF-β) gene. J Immunol 47:1053–1059
Udalova IA, Nedospasov SA, Webb GC, Chaplin DD, Turetskaya RL (1993) Highly informative typing of the human TNF locus using six adjacent polymorphic markers. Geno-mics 16: 180–186
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Cox, A., Gonzalez, A.M., Wilson, A.G. et al. Comparative analysis of the genetic associations of HLA-DR3 and tumour necrosis factor alpha with human IDDM. Diabetologia 37, 500–503 (1994). https://doi.org/10.1007/s001250050138
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DOI: https://doi.org/10.1007/s001250050138