THE HOXD8-LOCUS-(2Q31) IS LINKED TO TYPE-I DIABETES - INTERACTION WITH CHROMOSOME-6 AND CHROMOSOME-11 DISEASE SUSCEPTIBILITY GENES

Type I diabetes susceptibility genes have been identified within the m ajor histocompatibility complex (MHC) on chromosome 6p21.3 and near th e VNTR/insulin region on chromosome 11p15.5. We have used polymorphic dinucleotide repeat markers to search the human genome for additional susceptibility genes in 162 type I diabetic families with an affected sibling pair. We report that an additional susceptibility gene is loca ted on chromosome 2q31 near HOXD8 (P < 10(-5), maximum logarithm of od ds score = 4.8) in an analysis of affected sibling pairs having specif ic human leukocyte antigen (HLA) and hypervariable nucleotide tandem r epeat (VNTR)/insulin gene haplotypes (absence of high-risk HLA-DR3/4 h aplotypes and presence of homozygous high-risk class I VNTR alleles). These results suggest the interaction of a minimum of three genes in t he pathogenesis of type I diabetes in humans.