MULTIPLE DNA VARIANT ASSOCIATION ANALYSIS - APPLICATION TO THE INSULIN GENE REGION IN TYPE-I DIABETES

Association and linkage studies have shown that at least one of the ge netic factors involved in susceptibility to insulin-dependent diabetes mellitus (IDDM) is contained within a 4.1-kb region of the insulin ge ne. Sequence analysis has led to the identification of 10 DNA variants in this region that are associated with increased risk for IDDM. Thes e variants are in strong linkage disequilibrium with each other, and p revious studies have failed to distinguish between the variant(s) that cause increased susceptibility to IDDM and others that are associated with the disease because of linkage disequilibrium. To address this p roblem, we have undertaken a large population study of French diabetic s and controls and have analyzed genotype patterns for several of the variant sites simultaneously. This has led to the identification of a subset consisting of four variants (-2733AC, -23HphI, -365VNTR, and +1 140AC), at least one of which appears to be directly implicated in dis ease susceptibility. The multiple-DNA-variant association-analysis app roach that is applied here to the problem of identifying potential sus ceptibility variants in IDDM is likely to be important in studies of m any other multifactorial diseases.