The HLA-DPB1-associated component of the IDDM1 and its relationship to themajor loci HLA-DQB1,-DQA1, and-DRB1

The major histocompatibility complex (MHC) HLA region on chromosome 6p21 co ntains the major locus of type 1 diabetes (IDDM1). Common allelic variants at the class II HLA-DRB1, -DQA1, and -DQB1 loci account for the major part of IDDM1. Previous studies suggested that other MHC loci are likely to cont ribute to IDDM1, but determination of their relative contributions and iden tities is difficult because of strong Linkage disequilibrium between MHC lo ci. One prime candidate is the polymorphic HLA-DPB1 locus, which (with the DPA1 locus) encodes the third class II antigen-presenting molecule. However , the results obtained in previous studies appear to be contradictory. Ther efore, we have analyzed 408 white European families (200 from Sardinia and 208 hom the U.K.) using a combination of association tests designed to dire ctly compare the effect of DPB1 variation on the relative predisposition of DR-DQ haplotypes, taking into account linkage disequilibrium between DPB1 and the DRB1, DQA1, and DQB1 loci. In these populations, the overall contri bution of DPB1 to IDDM1 is small. The main component of the DPB1 contributi on to IDDM1 in these populations appears to be the protection associated wi th DPB1*0402 on DR4-negative haplotypes. me suggest that the HLA-DP molecul e itself contributes to IDDM1.