EVIDENCE OF A NON-MHC SUSCEPTIBILITY LOCUS IN TYPE-I DIABETES LINKED TO HLA ON CHROMOSOME-6

Linkage studies have led to the identification of several chromosome r egions that may contain susceptibility loci to type I diabetes (IDDM), in addition to the HLA and INS loci. These include two on chromosome 6q, denoted IDDM5 and IDDM8, that are not linked to HLA. In a previous study, we noticed that the evidence for linkage to IDDM susceptibilit y around the HLA locus extended over a total distance of 100 cM, which suggested to us that another susceptibility locus could reside near H LA. We developed a statistical method to test this hypothesis in a pan el of 523 multiplex families from France, the United States, and Denma rk (a total of 667 affected sib pairs, 536 with both parents genotyped ), and here present evidence (P = .0003) of a susceptibility locus for IDDM located 32 cM from HLA in males but not linked to HLA in females and distinct from IDDM5 and IDDM8. A new statistical method to test f or the presence of a second susceptibility locus linked to a known fir st susceptibility locus (here HLA) is presented. In addition, we analy zed our current family panel with markers for IDDM5 and IDDM8 on chrom osome 6 and found suggestions of linkage for both of these loci (P = . 002 and .004, respectively, on the complete family panel). When cumula ted with previously published results, with overlapping families remov ed, the affected-sib-pair tests had a significance of P = .0001 for ID DM5 and P = .0004 for IDDM8.