Skip to main content
NCBI home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1995 May;56(5):1080–1087.

Testing parental imprinting in insulin-dependent diabetes mellitus by the marker-association-segregation-chi 2 method.

P Margaritte-Jeannin 1, F Clerget-Darpoux 1, J Hors 1, I Deschamps 1
PMCID: PMC1801436  PMID: 7726162

Abstract

Among patients with insulin-dependent diabetes mellitus (IDDM), an excess of DR3 and DR4 alleles is classically described when compared with the general population. In addition, an excess of maternal DR3 and paternal DR4 alleles among patients (DR3DR4) is observed. In order to explain these observations, two alternative hypotheses can be tested: maternal effect and parental imprinting. Maternal effect has been tested and not rejected on a sample of 416 caucasians affected with IDDM. Under this hypothesis, the children of a DR3 mother are expected to have an earlier exposure and, hence, an earlier age at onset. However, we did not observe such a difference in age at onset in this data set. Using the marker-association-segregation-chi 2 method, we have tested four hypotheses with different parental effects of two susceptibility alleles, alpha 0 and beta 0, at two different closely linked loci. Under the hypothesis that best fitted the data, the probability of being affected depended on the parental inheritance of the susceptibility alleles, suggesting parental imprinting (i.e., differential role of maternal and paternal allele), without evidence for a cis-trans effect. We conclude that parental imprinting on a specific allelic combination may explain the observations on the HLA genotypes of the patients and their relatives.

Full text

PDF
1080

Selected References

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

  1. Bain S. C., Prins J. B., Hearne C. M., Rodrigues N. R., Rowe B. R., Pritchard L. E., Ritchie R. J., Hall J. R., Undlien D. E., Ronningen K. S. Insulin gene region-encoded susceptibility to type 1 diabetes is not restricted to HLA-DR4-positive individuals. Nat Genet. 1992 Nov;2(3):212–215. doi: 10.1038/ng1192-212. [DOI] [PubMed] [Google Scholar]
  2. 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]
  3. Clerget-Darpoux F., Babron M. C., Deschamps I., Hors J. Complementation and maternal effect in insulin-dependent diabetes. Am J Hum Genet. 1991 Jul;49(1):42–48. [PMC free article] [PubMed] [Google Scholar]
  4. Clerget-Darpoux F., Babron M. C., Prum B., Lathrop G. M., Deschamps I., Hors J. A new method to test genetic models in HLA associated diseases: the MASC method. Ann Hum Genet. 1988 Jul;52(Pt 3):247–258. doi: 10.1111/j.1469-1809.1988.tb01102.x. [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. Davies J. L., Kawaguchi Y., Bennett S. T., Copeman J. B., Cordell H. J., Pritchard L. E., Reed P. W., Gough S. C., Jenkins S. C., Palmer S. M. A genome-wide search for human type 1 diabetes susceptibility genes. Nature. 1994 Sep 8;371(6493):130–136. doi: 10.1038/371130a0. [DOI] [PubMed] [Google Scholar]
  7. Deschamps I., Hors J., Clerget-Darpoux F., Gardais E., Robert J. J., Marcelli-Berge A., Lestradet H., Dausset J. Excess of maternal HLA-DR3 antigens in HLA DR3,4 positive type 1 (insulin-dependent) diabetic patients. Diabetologia. 1990 Jul;33(7):425–430. doi: 10.1007/BF00404094. [DOI] [PubMed] [Google Scholar]
  8. Field L. L., Tobias R., Magnus T. A locus on chromosome 15q26 (IDDM3) produces susceptibility to insulin-dependent diabetes mellitus. Nat Genet. 1994 Oct;8(2):189–194. doi: 10.1038/ng1094-189. [DOI] [PubMed] [Google Scholar]
  9. Giannoukakis N., Deal C., Paquette J., Goodyer C. G., Polychronakos C. Parental genomic imprinting of the human IGF2 gene. Nat Genet. 1993 May;4(1):98–101. doi: 10.1038/ng0593-98. [DOI] [PubMed] [Google Scholar]
  10. Giddings S. J., King C. D., Harman K. W., Flood J. F., Carnaghi L. R. Allele specific inactivation of insulin 1 and 2, in the mouse yolk sac, indicates imprinting. Nat Genet. 1994 Mar;6(3):310–313. doi: 10.1038/ng0394-310. [DOI] [PubMed] [Google Scholar]
  11. Haig D. Is human insulin imprinted? Nat Genet. 1994 May;7(1):10–10. doi: 10.1038/ng0594-10a. [DOI] [PubMed] [Google Scholar]
  12. Hall J. G. Genomic imprinting: review and relevance to human diseases. Am J Hum Genet. 1990 May;46(5):857–873. [PMC free article] [PubMed] [Google Scholar]
  13. Hashimoto L., Habita C., Beressi J. P., Delepine M., Besse C., Cambon-Thomsen A., Deschamps I., Rotter J. I., Djoulah S., James M. R. Genetic mapping of a susceptibility locus for insulin-dependent diabetes mellitus on chromosome 11q. Nature. 1994 Sep 8;371(6493):161–164. doi: 10.1038/371161a0. [DOI] [PubMed] [Google Scholar]
  14. Julier C., Hyer R. N., Davies J., Merlin F., Soularue P., Briant L., Cathelineau G., Deschamps I., Rotter J. I., Froguel P. Insulin-IGF2 region on chromosome 11p encodes a gene implicated in HLA-DR4-dependent diabetes susceptibility. Nature. 1991 Nov 14;354(6349):155–159. doi: 10.1038/354155a0. [DOI] [PubMed] [Google Scholar]
  15. McCarthy B. J., Dorman J. S., Aston C. E. Investigating genomic imprinting and susceptibility to insulin-dependent diabetes mellitus: an epidemiologic approach. Genet Epidemiol. 1991;8(3):177–186. doi: 10.1002/gepi.1370080304. [DOI] [PubMed] [Google Scholar]
  16. Nicholls R. D. New insights reveal complex mechanisms involved in genomic imprinting. Am J Hum Genet. 1994 May;54(5):733–740. [PMC free article] [PubMed] [Google Scholar]
  17. Prum B., Guilloud-Bataille M., Clerget-Darpoux F. On the use of chi 2 tests for nested categorized data. Ann Hum Genet. 1990 Oct;54(Pt 4):315–320. doi: 10.1111/j.1469-1809.1990.tb00387.x. [DOI] [PubMed] [Google Scholar]
  18. Reed M. L., Leff S. E. Maternal imprinting of human SNRPN, a gene deleted in Prader-Willi syndrome. Nat Genet. 1994 Feb;6(2):163–167. doi: 10.1038/ng0294-163. [DOI] [PubMed] [Google Scholar]
  19. SIMPSON N. E. The genetics of diabetes: A study of 233 families of juvenile diabetics. Ann Hum Genet. 1962 Jul;26:1–21. doi: 10.1111/j.1469-1809.1962.tb01305.x. [DOI] [PubMed] [Google Scholar]
  20. Spielman R. S., Baur M. P., Clerget-Darpoux F. Genetic analysis of IDDM: summary of GAW5 IDDM results. Genet Epidemiol. 1989;6(1):43–58. doi: 10.1002/gepi.1370060111. [DOI] [PubMed] [Google Scholar]
  21. Spielman R. S., McGinnis R. E., Ewens W. J. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet. 1993 Mar;52(3):506–516. [PMC free article] [PubMed] [Google Scholar]
  22. Thomson G. HLA disease associations: models for insulin dependent diabetes mellitus and the study of complex human genetic disorders. Annu Rev Genet. 1988;22:31–50. doi: 10.1146/annurev.ge.22.120188.000335. [DOI] [PubMed] [Google Scholar]
  23. 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]
  24. Wagener D. K., Sacks J. M., LaPorte R. E., Macgregor J. M. The Pittsburgh study of insulin-dependent diabetes mellitus. Risk for diabetes among relatives of IDDM. Diabetes. 1982 Feb;31(2):136–144. doi: 10.2337/diab.31.2.136. [DOI] [PubMed] [Google Scholar]
  25. Zhang Y., Shields T., Crenshaw T., Hao Y., Moulton T., Tycko B. Imprinting of human H19: allele-specific CpG methylation, loss of the active allele in Wilms tumor, and potential for somatic allele switching. Am J Hum Genet. 1993 Jul;53(1):113–124. [PMC free article] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES