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American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1988 Jan;42(1):167–172.

Insulin-gene sharing in sib pairs with insulin-dependent diabetes mellitus: no evidence for linkage.

N J Cox 1, L Baker 1, R S Spielman 1
PMCID: PMC1715306  PMID: 2892397

Abstract

An association between insulin-dependent diabetes mellitus (IDDM) and an RFLP adjacent to the insulin gene has been consistently observed, but its etiological significance is unclear. We studied unrelated IDDM patients (N = 45) and controls (N = 65) to confirm the association--and assessed evidence for linkage in 22 families with at least two affected (IDDM) sibs--to determine whether the insulin-gene region actually contributes to susceptibility to IDDM. All individuals were typed for the RFLP in the 5'-flanking region of the insulin gene (5'FP) used in the previous studies, and the 12 families not fully informative for linkage with the 5'FP were typed for additional closely linked RFLPs. We found a higher frequency of class 1 alleles of the 5'FP in IDDM patients (.83) than in controls (.75), which is consistent with the reported association, but the difference was not statistically significant in our sample. Among the 33 affected sib pairs (ASPs) in 22 families, if maximum possible sharing is assumed when sharing is ambiguous, 10 pairs share both parental insulin genes, 17 pairs share one, and six share neither. This distribution is incompatible with close linkage. In contrast, for the HLA region, for which all 22 families are fully informative, 19 of the 33 ASPs share two haplotypes and the remaining 14 share one. There are no pairs that share neither HLA haplotype. Thus, although these data clearly illustrate the contribution of HLA-linked susceptibility to IDDM, they argue strongly against a contribution of similar magnitude by the insulin-gene region.

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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. Bell G. I., Karam J. H., Rutter W. J. Polymorphic DNA region adjacent to the 5' end of the human insulin gene. Proc Natl Acad Sci U S A. 1981 Sep;78(9):5759–5763. doi: 10.1073/pnas.78.9.5759. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bell G. I., Selby M. J., Rutter W. J. The highly polymorphic region near the human insulin gene is composed of simple tandemly repeating sequences. Nature. 1982 Jan 7;295(5844):31–35. doi: 10.1038/295031a0. [DOI] [PubMed] [Google Scholar]
  4. Chakravarti A., Elbein S. C., Permutt M. A. Evidence for increased recombination near the human insulin gene: implication for disease association studies. Proc Natl Acad Sci U S A. 1986 Feb;83(4):1045–1049. doi: 10.1073/pnas.83.4.1045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Clerget-Darpoux F., Bonaiti-Pellie C., Hors J., Deschamps I., Feingold N. Application of the lod score method to detection of linkage between HLA and juvenile insulin-dependent diabetes. Clin Genet. 1980 Jul;18(1):51–57. doi: 10.1111/j.1399-0004.1980.tb01365.x. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. Dizier M. H., Deschamps I., Hors J., Blanc M., Rivat L., Clerget-Darpoux F. Interactive effect of HLA and Gm tested in a study of 135 juvenile insulin-dependent diabetic families. Tissue Antigens. 1986 May;27(5):269–278. doi: 10.1111/j.1399-0039.1986.tb01532.x. [DOI] [PubMed] [Google Scholar]
  8. Elbein S. C., Corsetti L., Permutt M. A. New polymorphisms at the insulin locus increase its usefulness as a genetic marker. Diabetes. 1985 Nov;34(11):1139–1144. doi: 10.2337/diab.34.11.1139. [DOI] [PubMed] [Google Scholar]
  9. Ferns G. A., Hitman G. A., Trembath R., Williams L., Tarn A., Gale E. A., Galton D. J. DNA polymorphic haplotypes on the short arm of chromosome 11 and the inheritance of type I diabetes mellitus. J Med Genet. 1986 Jun;23(3):210–216. doi: 10.1136/jmg.23.3.210. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Green A., Svejgaard A., Platz P., Ryder L. P., Jakobsen B. K., Morton N. E., MacLean C. J. The genetic susceptibility to insulin-dependent diabetes mellitus: combined segregation and linkage analysis. Genet Epidemiol. 1985;2(1):1–15. doi: 10.1002/gepi.1370020102. [DOI] [PubMed] [Google Scholar]
  11. 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]
  12. Hodge S. E., Anderson C. E., Neiswanger K., Sparkes R. S., Rimoin D. L. The search for heterogeneity in insulin-dependent diabetes mellitus (IDDM): linkage studies, two-locus models, and genetic heterogeneity. Am J Hum Genet. 1983 Nov;35(6):1139–1155. [PMC free article] [PubMed] [Google Scholar]
  13. Hoover M. L., Angelini G., Ball E., Stastny P., Marks J., Rosenstock J., Raskin P., Ferrara G. B., Tosi R., Capra J. D. HLA-DQ and T-cell receptor genes in insulin-dependent diabetes mellitus. Cold Spring Harb Symp Quant Biol. 1986;51(Pt 2):803–809. doi: 10.1101/sqb.1986.051.01.093. [DOI] [PubMed] [Google Scholar]
  14. 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]
  15. 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]
  16. Schernthaner G., Mayr W. R. Immunoglobulin allotype markers and HLA DR genes in type I diabetes mellitus. Metabolism. 1984 Sep;33(9):833–836. doi: 10.1016/0026-0495(84)90110-0. [DOI] [PubMed] [Google Scholar]
  17. Spielman R. S., Baker L., Zmijewski C. M. Gene dosage and suceptibility to insulin-dependent diabetes. Ann Hum Genet. 1980 Oct;44(Pt 2):135–150. doi: 10.1111/j.1469-1809.1980.tb00954.x. [DOI] [PubMed] [Google Scholar]
  18. Suarez B. K., Hodge S. E. A simple method to detect linkage for rare recessive diseases: an application to juvenile diabetes. Clin Genet. 1979 Feb;15(2):126–136. doi: 10.1111/j.1399-0004.1979.tb01751.x. [DOI] [PubMed] [Google Scholar]
  19. Suarez B. K., Van Eerdewegh P. Type I (insulin dependent) diabetes mellitus. Is there strong evidence for a non-HLA linked gene? Diabetologia. 1981 May;20(5):524–529. doi: 10.1007/BF00252759. [DOI] [PubMed] [Google Scholar]
  20. Thomson G. A two locus model for juvenile diabetes. Ann Hum Genet. 1980 May;43(4):383–398. doi: 10.1111/j.1469-1809.1980.tb01572.x. [DOI] [PubMed] [Google Scholar]

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