EVIDENCE FOR OLIGOGENIC INHERITANCE OF TYPE-1 DIABETES IN A LARGE BEDOUIN ARAB FAMILY

Based on a genomic search for linkage, a locus contributing to type I diabetes in a large Bedouin Arab family (19 affected relatives) maps t o the long arm of chromosome 10 (10q25; nonparametric linkage = 4.99; P = 0.00004). All affected relatives carry one or two high-risk HLA-DR 3 haplotypes that are rarely found in other family members. One chromo some 10 haplotype, the B haplotype, was transmitted from a heterozygou s parent to 13 of 13 affected offspring compared to 10 of 23 unaffecte d siblings. Recombination events occurring on this haplotype place the susceptibility locus in an 8-cM interval between markers D10S1750 and D10S1773. Two adjacent markers, D10S592 and D10S554, showed evidence of linkage disequilibrium with the disease locus. A 273-bp allele at D 10S592 was transmitted to 8 of 10 affected offspring compared to 3 of 14 unaffected siblings, and a 151-bp allele at D10S554 was transmitted to 15 of 15 affected offspring compared with 10 of 24 unaffected sibl ings. D10S554 and D10S592 and the closest flanking markers are contain ed in a 1,240-kb yeast artificial chromosome, a region small enough to proceed with positional cloning.