The predisposition to type 1 diabetes linked to the human leukocyte antigen complex includes at least one non-class II gene

The human leukocyte antigen (HLA) complex, encompassing 3.5 Mb of DNA from the centromeric HLA-DPB2 locus to the telomeric HLA-F locus on chromosome 6 p21, encodes a major part of the genetic predisposition to develop type 1 d iabetes, designated "IDDM1." A primary role for allelic variation of the cl ass II HLA-DRB1, HLA-DQA1, and HLA-DQB1 loci has been established. However, studies of animals and humans have indicated that other, unmapped, major h istocompatibility complex (MHC)-linked genes are participating in IDDM1. Th e strong linkage disequilibrium between genes in this complex makes mapping a difficult task. In the present paper, we report on the approach we have devised to circumvent the confounding effects of disequilibrium between cla ss II alleles and alleles at other MHC loci. We have scanned 12 Mb of the M HC and flanking chromosome regions with microsatellite polymorphisms and an alyzed the transmission of these marker alleles to diabetic probands from p arents who were homozygous for the alleles of the HLA-DRB1, HLA-DQA1, and H LA-DQB1 genes. Our analysis, using three independent family sets, suggests the presence of an additional type I diabetes gene (or genes). This approac h is useful for the analysis of other loci linked to common diseases, to ve rify if a candidate polymorphism can explain all of the association of a re gion or if the association is due to two or more loci in linkage disequilib rium with each other.