Abstract
Insulin-dependent (type 1) diabetes mellitus (IDDM) is a multifactorial disease with a strong genetic component. The majority of the genetic component can be explained by associations between IDDM and genes in the major histocompatibility complex (MHC). The best single marker for IDDM is based on amino acid polymorphism of the HLA-DQ gene. Current evidence, however, indicates that the MHC susceptibility to IDDM is determined by a combination of HLA class I, II and III genes contained on HLA haplotypes. A non-MHC genetic component to IDDM also exists. To date, the most consistent association is between IDDM and markers of the insulin gene locus.
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Vague P . Environmental factors in the pathogenesis of insulin dependent and non-insulin dependent diabetes. In: Belfiore F, Galton DJ, Reavan GM, editors. Diabetes mellitus: etiopathogenesis and metabolic aspects. Frontiers in diabetes, vol. 4. Basel: Karger 1984:12–25.
Ginsberg-Fellner F, Witt ME, Yagihashi S, Dobersen MJ, Tunt F, Fedum B, et al. Congenital rubella syndrome as a model for type 1 (insulin-dependent) diabetes mellitus: increased prevalence of islet cell surface antibodies. Diabetologia 1984;(Suppl):87–9.
Karjalannen J, Morton JM, Krup M, Ilonen J, Robinson BH, Savilahti E, et al. A bovine albumin peptide as a possible trigger of insulin-dependent diabetes mellitus. N Engl J Med 1992;327:302–7.
Barnett AH, Eff C, Leslie RDG, Pyke DA . Diabetes in identical twins. Diabetologia 1981;20:87–93.
Gorsuch AN, Spencer KM, Wolf E, Cudworth AG . Insulin dependent diabetes mellitus: HLA and family studies. In: Kobberling J, Tattersall R, editors. The genetics of diabetes mellitus. Serona symposium 47. London: Academic Press, 1982:43–53.
Bottazzo GF, Dean BM, McNally JM, Mackay AE, Swift PGF, Gamble DG . In situ characterisation of autoimmune phenomena and expression of HLA molecules in the pancreas in diabetic insulitis. N Engl J Med 1985;313:353–60.
Nerup J, Cathelineau C, Seignalet J, Thomsen M . In: Daus-set J, Svejgaard, editors. HLA and disease. Copenhagen: Munksgaard, 1977:149–67.
Sachs JA, Cudworth AG, Jaruquemada D, Gorsuch AN, Festenstein H . Type 1 diabetes and the HLA D locus. Diabetologia 1980;418:41–3.
Sveggaard A, Platz P, Ryder LP In: Terasaki PI, editor. His-tocompatibility testing 1980. Los Angeles: Tissue Typing Laboratory, 1980:638–54.
Wolf E, Spencer KM, Cudworth AG . The genetic susceptibility to type 1 (insulin dependent) diabetes: analysis of the HLA-DR association. Diabetologia 1984;24:224–30.
Todd JA, Bell JI, McDevitt HO . HLA-DQβ gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature 1987;329:599–604.
Khalil I, d'Aurrol L, Gebet M, et al. A combination of HLA-DQ beta Asp 57 negative and HLA DQ alpha Arg 52 confers susceptibility to insulin dependent diabetes mellitus. J Clin Invest 1990;85:1315–6.
Green A, Gale EAM, Patterson CC (for the Eurodiab Ace Study Group). Incidence of childhood-onset insulin dependent diabetes mellitus: the Eurodiab Ace study. Lancet 1992;339:905–9.
Nepom BS, Schwarz D, Palmer JP, Nepom GT . Transcom-plementation of HLA genes in IDDM HLA DQα and β chains produced hybrid molecules in DR3/4 heterozygotes. Diabetes 1987;36:114–7.
Tuomilehto-Wolf E, Tuomilehto J, and the DiMe Study Group. DR3, DR4 heterozygosity is not the reason for the high incidence of IDDM in Finland. Diabetes 1990;39(Suppl 1):21.
Raum D, Awdeh Z, Yams EJ, Alper CA, Gabay KH . Extended major histocompatibility complex haplotypes in type 1 diabetes mellitus. J Clin Invest 1984;74:449–54.
Tuomilehto-Wolf E, Tuomilehto J, Cepalkis Z, Lounamaa R and the DiMe Study Group. New susceptibility haplotype for type 1 diabetes. Lancet 1989;2:299–302.
Tienari PJ, Tuomilehto-Wolf E, Tuomilehto J, Peltonen L and the DiMe Study Group. HLA haplotypes in type 1 (insulin-dependent) diabetes mellitus: molecular analysis of the HLA-DQ locus. Diabetologia 1992;35:254–60.
Bjorkman PJ, Saper MA, Samraoui B, Bennett WS, Strom-inger IL, Wiley DC . The foreign antigen binding site and T cell recognition region of class I histocompatibility antigens. Nature 1987;329:512–8.
Jacob CO, Fronek Z, Lewis GD, Koo M, Hansen JA, McDevitt HO . Heritable major histocompatibility complex class II. Associated differences in production of tumour necrosis factor α: relevance to genetic predisposition to systemic lupus erythematosus. Proc Natl Acad Sci USA 1990;87:1233–7.
Poicot F, Molvig J, Wogensen L, Worsage H, Dalboge H, Back L, Nerup J . A tumour necrosis factor beta gene polymorphism in relation to monokine secretion and insulin dependent diabetes mellitus. Scand J Immunol 1991;33:37–49.
Foulis AK, Farquharson, Hardman R . Aberrant expression of class II major histocompatibility complex molecules by B cells and hyperexpression of class I major histocompatibility complex molecules by insulin containing islets in type 1 (insulin-dependent) diabetes mellitus. Diabetologia 1987;30:333–43.
Santamaria P, Nakhleh RE, Sutherland DE, Barbosa JJ . Characterisation of T lymphocytes infiltrating human pancreas allograft affected by isletitis and recurrent diabetes. Diabetes 1992;41:53–61.
Hitman GA, McCarthy MI . Genetics of NIDDM. In: Harrison L, Tait B, editors. Bailliere's clinical endocrinology and metabolism, vol. 5. Eastbourne: Bailliere Tindall 1991:445–76.
Kambo PK, Hitman GA, Mohan V, Ramachandran A, Sne-halatha C, Suresh S, et al. The genetic predisposition to fibrocalculous pancreatic diabetes. Diabetologia 1989;32:45–51.
Rotter JI, Landaw EM . Measuring the genetic contribution of a single locus to a multilocus disease. Clin Genet 1984;26:529–42.
Bell GI, Horita S, Karam JH . A highly polymorphic locus near the human insulin gene is associated with insulin dependent diabetes mellitus. Diabetes 1984;33:176–83.
Hitman GA, Tarn AC, Winter RM, Drummond V, Williams LG, Jowett NI, et al. Type 1 (insulin dependent) diabetes and a highly variable locus close to the insulin gene on chromosome 11. Diabetologia 1985;28:218–22.
Julier C, Hyer RN, Davies J, Merlin F, Soularne P, Bryant L, et al. Insulin-IGF2 region on chromosome 11p encodes a gene implicated in HLA-DR4 dependent diabetes susceptibility. Nature 1991;354:155–9.
Hitman GA, Toms GC, Boucher BJ, Garde L, Baker P, Awad J, Festenstein H . 2′, 5′ -oligodenylate synthetase and its relationship to HLA and genetic markers of insulin dependent diabetes mellitus. Immunogenetics 1989;30:427–31.
Raffel LJ, Rotter JI, Hitman GA, Toyoda H, Karam JH, Yen PH, Bell GI . The aggregation of the 5′ insulin gene polymorphism in type 1 (insulin dependent) diabetes mellitus families. J Med Genet 1992;29:447–50.
Owerbach D, Gunn S, Gabbay KH . Multigenic basis for type 1 diabetes: association of HRAS1 polymorphism with HLA DR3, DQw2/DR4 DQw8. Diabetes 1990;39:1504–9.
Hoover ML, Capra JD . HLA and T cell receptor genes in insulin-dependent diabetes mellitus. Diabetes Metab Rev 1987;3:835–56.
Millward BA, Welsh KI, Leslie RDG, et al. T cell receptor beta chain polymorphisms are associated with insulin-dependent diabetes. Clin Exp Immunol 1987;70:152–7.
Niven MJ, Caffrey C, Moore RH, Sachs JA, Mohan V, Fes-tenstein H, et al. T cell receptor β subunit gene polymorphism and autoimmune disease. Hum Immunol 1990;27:360–7.
Field LL, Anderson CE, Neisenanger K, et al. Interaction of HLA and immunoglobulin antigens in type 1 (insulin-dependent) diabetes. Diabetologia 1984;27:504–8.
Schernthaner G, Mayr WR . Immunoglobulin allotype markers and HLA-DR genes in type 1 diabetes mellitus. Metabolism 1984;33:833–6.
Hawrami K, Mohan R, Mohan V, Hitman GA . A genetic study of retinopathy in South Indian non-insulin dependent diabetics. Diabetologia 1991;34:441–4.
Patel A, Ratanachaiyavong S, Millward BA, Demaine AG . A polymorphism of the aldose reductase locus is a predictive marker of diabetic retinopathy. Diabetologia 1992;35(Suppl 1):A63.
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Hitman, G. The immunogenetics of insulin-dependent diabetes. Eye 7, 209–213 (1993). https://doi.org/10.1038/eye.1993.50
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DOI: https://doi.org/10.1038/eye.1993.50
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