, Volume 38, Issue 6, pp 715–719 | Cite as

Parental imprinting effect at the INS-IGF2 diabetes susceptibility locus

  • C. Polychronakos
  • A. Kukuvitis
  • N. Giannoukakis
  • E. Colle


Although association of insulin-dependent diabetes mellitus with a haplotype at a locus encompassing the genes for insulin and the insulin-like growth factor II has been well established, two major studies disagree as to whether linkage to this locus is confined to paternally inherited alleles, or is present in alleles transmitted from either parental sex. Towards resolving this discrepancy, we examined parent-of-origin specific association rather than linkage, using the haplotype relative risk method in a mixed Caucasian population. We find that the haplotype relative risk (HRR) conferred by paternal chromosomes was much higher (5.1, p<0.01) than the corresponding maternal value (2.3, p=0.07), which narrowly failed to reach statistical significance. Thus, although we cannot exclude an effect of the maternal allele, such an effect appears to be considerably weaker. We review evidence that parental imprinting is genotype-dependent, which may explain the different degrees to which the paternal effect is seen in different populations.

Key words

Genetic association imprinting insulin insulin-like growth factor II 



Insulin-dependent diabetes mellitus


restriction fragment length polymorphism


insulin gene


gene for the insulin-like growth factor II


haplotype relative risk


odds ratio


relative risk


  1. 1.
    Risch N (1987) Assessing the role of HLA-linked and unlinked determinants of disease. Am J Hum Genet 40: 1–14Google Scholar
  2. 2.
    Julier C, Hyer RN, Davies J et al. (1991) Insulin-IGF2 region on chromosome 11 p encodes a gene implicated in HLA-DR4-dependent diabetes susceptibility. Nature 354 (14): 155–159Google Scholar
  3. 3.
    Lucassen AM, Julier C, Beressi JP et al. (1993) Susceptibility to IDDM maps to a 4.8 kb segment of DNA spanning the insulin gene and associated VNTR. Nature Genetics 4: 305–310Google Scholar
  4. 4.
    Bain SC, Prins JB, Hearne CM et al. (1992) Insulin gene region-encoded susceptibility to type 1 diabetes is not restricted to HLA-DR4-positive indivuals. Nature Genetics 2: 212–215Google Scholar
  5. 5.
    Tadokoro K, Fujii H, Inoue T, Yamada M (1991) Polymerase chain reaction (PCR) for detection of Apal polymorphism at the insulin like growth factor II gene (IGF2). Nucleic Acids Res 19: 6967Google Scholar
  6. 6.
    Field LL, Fothergill-Payne C, Bertrams J, Baur MP (1986) HLA-DR effects in a large German IDDM dataset. Genet Epidemiol 1 [Suppl]: 323–328Google Scholar
  7. 7.
    Falk CT, Rubinstein P (1987) Haplotype relative risks: an easy, reliable way to to construct a proper control sample for risk calculations. Ann Hum Genet 51: 227–233Google Scholar
  8. 8.
    Knapp M, Seuchter SA, Baur MP (1993) The haplotype-relative-risk (HRR) method for analysis of association in nuclear families. Am J Hum Genet 52: 1085–1093Google Scholar
  9. 9.
    Fleiss JL (1981) Statistical methods for rates and proportions. (2nd edn.) John Wiley, New YorkGoogle Scholar
  10. 10.
    Gart JJ (1962) On the combination of relative risks. Biometrics 18: 601–610Google Scholar
  11. 11.
    Warram JH, Krolewski AS, Gottlieb MS, Kahn CR (1984) Differences in risk of insulin-dependent diabetes in offspring of diabetic mothers and diabetic fathers. N Engl J Med 1: 149–152Google Scholar
  12. 12.
    Hall JG (1990) Genomic imprinting review and relevance to human diseases. Am J Hum Genet 46: 857–873Google Scholar
  13. 13.
    Giannoukakis N, Deal C, Goodyer CG, Paquette J, Polychronakos C (1993) Parental genomic imprinting of the human IGF2 gene. Nature Genetics 4: 98–101Google Scholar
  14. 14.
    Giddings SJ, King CD, Harman KW, Flood JF, Carnaghi LR (1994) Allele specific inactivation of insulin 1 and 2, in the mouse yolk sac, indicates imprinting. Nature Genetics 6 (3): 310–313Google Scholar
  15. 15.
    Gabbay KH, DeLuca K, Fisher JN Jr, Mako ME, Rubenstein AH (1976) Familial hyperproinsulinemia. An autosomal dominant defect. N Engl J Med 294: 911–915Google Scholar
  16. 16.
    Nyman T, Peknonen F (1993) The expression of IGFs and their binding proteins in normal human lymphocytes. Acta Endocrinol 128: 168–172Google Scholar
  17. 17.
    Hill DJ, Hogg J (1992) Expression of insulin-like growth factors and their binding proteins during pancreatic development in rat, and modulation of IGF actions on rat islet DNA synthesis by IGF BPs. Adv Exp Med Biol 321: 113–120Google Scholar
  18. 18.
    Allen ND, Norris ML, Surani MA (1990) Epigenetic control of transgene expression and imprinting by genotype-specific modifiers. Cell 61: 853–861Google Scholar
  19. 19.
    Sapienza C, Paquette J, Tran TH, Peterson A (1989) Epigenetic and genetic factors affect transgene methylation imprinting. Development 107: 165–186Google Scholar
  20. 20.
    Xu Y, Goodyer CG, Deal C, Polychronakos C (1993) Functional polymorphism in the parental imprinting of the human IGF2R gene. Biochem Biophys Res Commun 197: 747–754Google Scholar
  21. 21.
    Hodge E (1993) Linkage analysis versus association analysis. Distinguishing between two models that explain disease-marker associations. Am J Hum Gen 53: 367–384Google Scholar
  22. 22.
    Cooperative Human Linkage Center, Genethon, University of Utah, Yale University and CEPH (1994) A comprehensive human linkage map with centimorgan density. Science 265: 2049–2070Google Scholar

Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • C. Polychronakos
    • 1
  • A. Kukuvitis
    • 1
  • N. Giannoukakis
    • 1
  • E. Colle
    • 1
  1. 1.Montreal Children's Hospital Research Institute, Department of Pediatrics, Division of EndocrinologyMcGill UniversityMontrealCanada

Personalised recommendations