Definition of IDDM-associated HLA DQ and DX RFLPs by segregation analysis of multiplex sibships

Abstract Genetic variation of the DQα and β and of the DXα genes, detectable as RFLP in genomic DNA digests, has been suggested to improve the identification of individuals at high risk for insulin-dependent diabetes mellitus (IDDM). DNA from all members of 32 IDDM multiplex families was digested with six restriction endonucleases and the resulting fragments analyzed in Southern blots for hybridization with labeled cDNA probes for those genes. A computerized segregation analysis procedure was then used to assign fragments to haplotypes. Associations among fragments and between fragments and haplotypes characterized serologically and biochemically for their class II genes and IDDM-carrier status were calculated. The results indicate that the alleles of the DXα polymorphism maintain linkage disequilibrium with those of the DQβ genes responsible for the well-known DQβ3.2-IDDM association, so that IDDM-carrier haplotypes carry disproportionally often both DQβ3.2 and DXα-TaqI-2.2kb. Thus, these RFLPs identify a DR-DQ-DX haplotype in high linkage disequilibrium, rather than the locus or loci that account for their high relative risk. However, four DR4-DQβ3.2 haplotypes that lack DXα-TaqI-2.2kb were encountered, two of which are “affected”. These haplotypes suggest that the identification of the “disease locus” can be facilitated by the study of unusual haplotypes in which distinct IDDM-associated alleles occur separated from their neighbors of the standard genetic configurations.