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. 1992 Jul;29(7):447–450.

The aggregation of the 5' insulin gene polymorphism in insulin dependent (type I) diabetes mellitus families.

L J Raffel 1, G A Hitman 1, H Toyoda 1, J H Karam 1, G I Bell 1, J I Rotter 1
PMCID: PMC1016016  PMID: 1353534

Abstract

Population studies have suggested an increased frequency of small DNA insertions (class I alleles) 5' to the insulin gene in insulin dependent (type I) diabetes mellitus (IDDM). The present study examined this relationship within families. Forty-one families with at least one diabetic offspring were studied. Analysis of the insulin gene polymorphism was performed by digestion of DNA with Bg1I, SstI, RsaI, or PvuII and hybridisation with an insulin gene probe or polymorphic region specific probes. An increased frequency of class I alleles was found among the parents of diabetics (p = 0.02), as well as a trend towards increased frequency of parents homozygous for class I alleles and matings of two homozygous subjects. This increased homozygosity for class I alleles was present in non-diabetic sibs as well (p = 0.01). These results show that ascertainment through an offspring with IDDM selects for families with high frequencies of homozygosity for the class I allele and thus suggests that the insulin gene polymorphism is indeed providing part of the genetic predisposition to IDDM. When the major portion of genetic predisposition is provided by other genes (estimates are that HLA accounts for 30 to 70% in IDDM), identification of additional susceptibility genes becomes difficult. Even when formal linkage analysis is uninformative, our studies indicate that analysis for aggregation of specific alleles within families is a useful approach to this problem.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bell G. I., Horita S., Karam J. H. A polymorphic locus near the human insulin gene is associated with insulin-dependent diabetes mellitus. Diabetes. 1984 Feb;33(2):176–183. doi: 10.2337/diab.33.2.176. [DOI] [PubMed] [Google Scholar]
  2. Colle E., Guttmann R. D., Seemayer T. A., Michel F. Spontaneous diabetes mellitus syndrome in the rat. IV. Immunogenetic interactions of MHC and non-MHC components of the syndrome. Metabolism. 1983 Jul;32(7 Suppl 1):54–61. doi: 10.1016/s0026-0495(83)80012-2. [DOI] [PubMed] [Google Scholar]
  3. Cox N. J., Baker L., Spielman R. S. Insulin-gene sharing in sib pairs with insulin-dependent diabetes mellitus: no evidence for linkage. Am J Hum Genet. 1988 Jan;42(1):167–172. [PMC free article] [PubMed] [Google Scholar]
  4. Cox N. J., Spielman R. S. The insulin gene and susceptibility to IDDM. Genet Epidemiol. 1989;6(1):65–69. doi: 10.1002/gepi.1370060113. [DOI] [PubMed] [Google Scholar]
  5. Cudworth A. G., Woodrow J. C. Evidence for HL-A-linked genes in "juvenile" diabetes mellitus. Br Med J. 1975 Jul 19;3(5976):133–135. doi: 10.1136/bmj.3.5976.133. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Dizier M. H., Clerget-Darpoux F., Hochez J. Segregation analysis of two genetic markers in IDDM families under two-locus models. Genet Epidemiol. 1989;6(1):71–75. doi: 10.1002/gepi.1370060114. [DOI] [PubMed] [Google Scholar]
  7. Donald J. A., Barendse W., Cooper D. W. Linkage studies of HLA and insulin gene restriction fragment length polymorphisms in families with IDDM. Genet Epidemiol. 1989;6(1):77–81. doi: 10.1002/gepi.1370060115. [DOI] [PubMed] [Google Scholar]
  8. Easton D. F. Linkage analysis and genetic models for IDDM. Genet Epidemiol. 1989;6(1):83–88. doi: 10.1002/gepi.1370060116. [DOI] [PubMed] [Google Scholar]
  9. Falk C. T., Rubinstein P. Haplotype relative risks: an easy reliable way to construct a proper control sample for risk calculations. Ann Hum Genet. 1987 Jul;51(Pt 3):227–233. doi: 10.1111/j.1469-1809.1987.tb00875.x. [DOI] [PubMed] [Google Scholar]
  10. Field L. L., Dizier M. H., Anderson C. E., Spence M. A., Rotter J. I. HLA-dependent GM effects in insulin-dependent diabetes: evidence from pairs of affected siblings. Am J Hum Genet. 1986 Nov;39(5):640–647. [PMC free article] [PubMed] [Google Scholar]
  11. Field L. L. Insulin-dependent diabetes mellitus: a model for the study of multifactorial disorders. Am J Hum Genet. 1988 Dec;43(6):793–798. [PMC free article] [PubMed] [Google Scholar]
  12. Fimmers R., Neugebauer M., Dennert J., Wienker T., Baur M. P. Association and sibpair analysis for the HLA, Gm, Km, and insulin polymorphisms in multiplex IDDM families. Genet Epidemiol. 1989;6(1):107–112. doi: 10.1002/gepi.1370060120. [DOI] [PubMed] [Google Scholar]
  13. Hitman G. A., Tarn A. C., Winter R. M., Drummond V., Williams L. G., Jowett N. I., Bottazzo G. F., Galton D. J. Type 1 (insulin-dependent) diabetes and a highly variable locus close to the insulin gene on chromosome 11. Diabetologia. 1985 Apr;28(4):218–222. doi: 10.1007/BF00282236. [DOI] [PubMed] [Google Scholar]
  14. Hoover M. L., Capra J. D. HLA and T-cell receptor genes in insulin-dependent diabetes mellitus. Diabetes Metab Rev. 1987 Jul;3(3):835–856. doi: 10.1002/dmr.5610030312. [DOI] [PubMed] [Google Scholar]
  15. Ito M., Tanimoto M., Kamura H., Yoneda M., Morishima Y., Takatsuki K., Itatsu T., Saito H. Association of HLA-DR phenotypes and T-lymphocyte-receptor beta-chain-region RFLP with IDDM in Japanese. Diabetes. 1988 Dec;37(12):1633–1636. doi: 10.2337/diab.37.12.1633. [DOI] [PubMed] [Google Scholar]
  16. Maclaren N., Riley W., Skordis N., Atkinson M., Spillar R., Silverstein J., Klein R., Vadheim C., Rotter J. Inherited susceptibility to insulin-dependent diabetes is associated with HLA-DR1, while DR5 is protective. Autoimmunity. 1988;1(3):197–205. doi: 10.3109/08916938808997164. [DOI] [PubMed] [Google Scholar]
  17. Millward B. A., Welsh K. I., Leslie R. D., Pyke D. A., Demaine A. G. T cell receptor beta chain polymorphisms are associated with insulin-dependent diabetes. Clin Exp Immunol. 1987 Oct;70(1):152–157. [PMC free article] [PubMed] [Google Scholar]
  18. Niven M. J., Caffrey C., Moore R. H., Sachs J. A., Mohan V., Festenstein H., Hoover M. L., Hitman G. A. T-cell receptor beta-subunit gene polymorphism and autoimmune disease. Hum Immunol. 1990 Apr;27(4):360–367. doi: 10.1016/0198-8859(90)90086-5. [DOI] [PubMed] [Google Scholar]
  19. Owerbach D., Gunn S., Gabbay K. H. Multigenic basis for type I diabetes. Association of HRAS1 polymorphism with HLA-DR3, DQw2/DR4, DQw8. Diabetes. 1990 Dec;39(12):1504–1509. doi: 10.2337/diab.39.12.1504. [DOI] [PubMed] [Google Scholar]
  20. Owerbach D., Nerup J. Restriction fragment length polymorphism of the insulin gene in diabetes mellitus. Diabetes. 1982 Mar;31(3):275–277. doi: 10.2337/diab.31.3.275. [DOI] [PubMed] [Google Scholar]
  21. Prochazka M., Leiter E. H., Serreze D. V., Coleman D. L. Three recessive loci required for insulin-dependent diabetes in nonobese diabetic mice. Science. 1987 Jul 17;237(4812):286–289. doi: 10.1126/science.2885918. [DOI] [PubMed] [Google Scholar]
  22. Rich S. S. Mapping genes in diabetes. Genetic epidemiological perspective. Diabetes. 1990 Nov;39(11):1315–1319. doi: 10.2337/diab.39.11.1315. [DOI] [PubMed] [Google Scholar]
  23. Rich S. S., Weitkamp L. R., Guttormsen S., Barbosa J. Gm, Km, and HLA in insulin-dependent type I diabetes mellitus. A log-linear analysis of association. Diabetes. 1986 Aug;35(8):927–932. doi: 10.2337/diab.35.8.927. [DOI] [PubMed] [Google Scholar]
  24. Risch N. Assessing the role of HLA-linked and unlinked determinants of disease. Am J Hum Genet. 1987 Jan;40(1):1–14. [PMC free article] [PubMed] [Google Scholar]
  25. Rotter J. I., Landaw E. M. Measuring the genetic contribution of a single locus to a multilocus disease. Clin Genet. 1984 Dec;26(6):529–542. doi: 10.1111/j.1399-0004.1984.tb01100.x. [DOI] [PubMed] [Google Scholar]
  26. Rotter J. I. The modes of inheritance of insulin-dependent diabetes mellitus or the genetics of IDDM, no longer a nightmare but still a headache. Am J Hum Genet. 1981 Nov;33(6):835–851. [PMC free article] [PubMed] [Google Scholar]
  27. Rotwein P. S., Chirgwin J., Province M., Knowler W. C., Pettitt D. J., Cordell B., Goodman H. M., Permutt M. A. Polymorphism in the 5' flanking region of the human insulin gene: a genetic marker for non-insulin-dependent diabetes. N Engl J Med. 1983 Jan 13;308(2):65–71. doi: 10.1056/NEJM198301133080202. [DOI] [PubMed] [Google Scholar]
  28. Southern E. M. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975 Nov 5;98(3):503–517. doi: 10.1016/s0022-2836(75)80083-0. [DOI] [PubMed] [Google Scholar]
  29. Thomson G., Robinson W. P., Kuhner M. K., Joe S., Klitz W. HLA and insulin gene associations with IDDM. Genet Epidemiol. 1989;6(1):155–160. doi: 10.1002/gepi.1370060129. [DOI] [PubMed] [Google Scholar]
  30. Thomson G., Robinson W. P., Kuhner M. K., Joe S., MacDonald M. J., Gottschall J. L., Barbosa J., Rich S. S., Bertrams J., Baur M. P. Genetic heterogeneity, modes of inheritance, and risk estimates for a joint study of Caucasians with insulin-dependent diabetes mellitus. Am J Hum Genet. 1988 Dec;43(6):799–816. [PMC free article] [PubMed] [Google Scholar]
  31. Todd J. A., Aitman T. J., Cornall R. J., Ghosh S., Hall J. R., Hearne C. M., Knight A. M., Love J. M., McAleer M. A., Prins J. B. Genetic analysis of autoimmune type 1 diabetes mellitus in mice. Nature. 1991 Jun 13;351(6327):542–547. doi: 10.1038/351542a0. [DOI] [PubMed] [Google Scholar]
  32. Vadheim C. M., Rotter J. I., Maclaren N. K., Riley W. J., Anderson C. E. Preferential transmission of diabetic alleles within the HLA gene complex. N Engl J Med. 1986 Nov 20;315(21):1314–1318. doi: 10.1056/NEJM198611203152103. [DOI] [PubMed] [Google Scholar]
  33. Vogelstein B., Gillespie D. Preparative and analytical purification of DNA from agarose. Proc Natl Acad Sci U S A. 1979 Feb;76(2):615–619. doi: 10.1073/pnas.76.2.615. [DOI] [PMC free article] [PubMed] [Google Scholar]

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