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Insulin-IGF2 region on chromosome 11p encodes a gene implicated in HLA-DR4-dependent diabetes susceptibility

Abstract

A CLASS of alleles at the VNTR (variable number of tandem repeat) locus in the 5' region of the insulin gene (INS) on chromosome 11p is associated with increased risk of insulin-dependent diabetes mellitus (IDDM)1–6, but family studies have failed to demonstrate linkage5,7. INS is thought to contribute to IDDM susceptibility but this view has been difficult to reconcile with the lack of linkage evidence6–8. We thus investigated polymorphisms of INS and neighbouring loci in random diabetics, IDDM multiplex families and controls. HLA-DR4-positive diabetics showed an increased risk associated with common variants at polymorphic sites in a 19-kilobase segment spanned by the 5' INS VNTR and the third intron of the gene for insulin-like growth factor II (IGF2). As INS is the major candidate gene from this region, diabetic and control sequences were compared to identify all INS polymorphisms that could contribute to disease susceptibility. In multiplex families the IDDM-associated alleles were transmitted preferentially to HLA-DR4-positive diabetic offspring from heterozygous parents. The effect was strongest in paternal meioses, suggesting a possible role for maternal imprinting. Our results strongly support the existence of a gene or genes affecting HLA-DR4 IDDM susceptibility which is located in a 19-kilobase region of INS-IGF2. Our results also suggest new ways to map susceptibility loci in other common diseases.

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References

  1. Bell, G. I., Horita, S. & Karam, J. H. Diabetes 33, 176–183 (1984).

    Article  CAS  PubMed  Google Scholar 

  2. Bell, G. I. et al. Am. J. hum. Genet. 37, A188 (1985).

    Google Scholar 

  3. Hitman, G. A. et al. Diabetologia 28, 218–222 (1985).

    Article  CAS  PubMed  Google Scholar 

  4. Ferns, G. A. et al. J. med. Genet. 23, 210–216 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Cox, N. J., Baker, L. & Spielman, R. S. Am. J. hum. Genet. 42, 167–172 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Thomson, G. et al. Genet. Epidemiol. 6, 155–160 (1989).

    Article  CAS  PubMed  Google Scholar 

  7. Cox, N. J. & Spielman, R. S. Genet. Epidemiol. 6, 65–69 (1989).

    Article  CAS  PubMed  Google Scholar 

  8. Spielman, R. S. et al. Genet Epidemiol. 6, 43–58 (1989).

    Article  CAS  PubMed  Google Scholar 

  9. Bell, G. I. et al. Nature 284, 26–32 (1980).

    Article  ADS  CAS  PubMed  Google Scholar 

  10. Sures, I., Goeddel, D. V., Gray, A. & Ullrich, A. Science 208, 57–59 (1980).

    Article  ADS  CAS  PubMed  Google Scholar 

  11. Ullrich, A., Dull, T. J., Gray, A. & Sures, I. Science 209, 612–615 (1980).

    Article  ADS  CAS  PubMed  Google Scholar 

  12. Bell, G. I., Selby, M. J. & Rutter, W. J. Nature 295, 31–35 (1982).

    Article  ADS  CAS  PubMed  Google Scholar 

  13. Ullrich, A. et al. Nucleic Acids Res. 10, 2225–2240 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bell, G. I., Karam, J. H. & Rutter, W. J. Proc. natn. Acad. Sci. U.S.A. 78, 5759–5763 (1981).

    Article  ADS  CAS  Google Scholar 

  15. Hitman, G. A., Kambo, P. K., Viswanathan, M. & Mohan, V. J. med. Genet. 27, 97–100 (1990).

    Google Scholar 

  16. Thomson, G. et al. Am. J. hum. Genet. 43, 799–816 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. DeChiara, T. M., Robertson, E. J. & Efstratiadis, A. Cell 64, 849–858 (1991).

    Article  CAS  PubMed  Google Scholar 

  18. Beechey, C. V., Cattanach, B. M. & Searle, A. G. Mouse Genome 87, 64–65 (1990).

    Google Scholar 

  19. Koufos, A. et al. Am. J. hum. Genet. 44, 711–719 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Brown, K. W., Williams, J. C., Maitland, N. J. & Mott, M. G. Am. J. hum. Genet. 46, 1000–1001 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Grunt, J. A. & Enriquez, A. R. Yale J. biol. Med. 45, 15–21 (1972).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Pettenati, M. J. et al. Hum. Genet. 74, 143–154 (1986).

    Article  CAS  PubMed  Google Scholar 

  23. Warram, J. H. et al. New Engl. J. Med. 311, 149–152 (1986).

    Article  ADS  Google Scholar 

  24. Cox, N. J., Bell, G. I. & Xiang, K-S Am. J. hum. Genet. 43, 495–501 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Bell, G. I. & Seino, S. in Molecular Biology of Islets of Langerhans (ed. Okamoto, H.), (Cambridge University Press, 1990).

    Google Scholar 

  26. Human Gene Mapping 10 Cytogenet. Cell Genet. 51, 1–1148 (1989).

  27. Human Gene Mapping 10.5 Cytogenet Cell Genet 55, 1–785 (1990).

  28. Hyer, R. N. et al. Am. J. hum. Genet. 48, 243–257 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Bell, G. I. et al. in Molecular Approaches to Polygenic Disease, Ciba Found. Symp. 130 (Wiley, Chichester, 1987).

    Google Scholar 

  30. Owerbach, D., Gunn, S. & Gabbay, K. H. Diabetes 39, 1504–1509 (1990).

    Article  CAS  PubMed  Google Scholar 

  31. Bidwell, J. L. et al. Transplantation 45, 640–646 (1988).

    Article  CAS  PubMed  Google Scholar 

  32. Dixon, W. J. et al. BMDP Statistical Software Manual (University of California Press, 1988).

    Google Scholar 

Download references

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Julier, C., Hyer, R., Davies, J. et al. Insulin-IGF2 region on chromosome 11p encodes a gene implicated in HLA-DR4-dependent diabetes susceptibility. Nature 354, 155–159 (1991). https://doi.org/10.1038/354155a0

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