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Letters to Nature

Nature 354, 155-159 (14 November 1991) | doi:10.1038/354155a0; Accepted 4 October 1991

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

C. Julier*, R. N. Hyer†, J. Davies*, F. Merlin*, P. Soularue*, L. Briant‡, G. Cathelineau§, I. Deschampsparallel, J. I. Rotter, P. Froguel*, §, C. Boitardparallel, J. I. Bell†, £ & G. M. Lathrop*

  1. * Centre d'Etude du Polymorphisme Humain, 27 rue Juliette Dodu, 75010 Paris, France
  2. † Molecular Immunology Group, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford 0X3 9DU, UK
  3. ‡ INSERM U100, Hôpital Purpan, Place du Docteur Baylac, 31059 Toulouse, France
  4. § Service d'endocrinologie, Hôpital St Louis, 2 Place du Docteur Fournier, 75010 Paris, France
  5. parallel INSERM U25, Hôpital Necker, 161 Rue de Sèvres, 75015 Paris, France
  6. Division of Medical Genetics, Cedars-Sinai Medical Center, and UCLA School of Medicine, Los Angeles, California 90048, USA
  7. £ To whom correspondence should be addressed.
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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.