ASSOCIATION OF LMP2 AND LMP7 GENES WITHIN THE MAJOR HISTOCOMPATIBILITY COMPLEX WITH INSULIN-DEPENDENT DIABETES-MELLITUS - POPULATION AND FAMILY STUDIES

LMP2 and LMP7, two subunits of the proteasomes encoded in the major hi stocompatibility complex, are speculated to play a role in the generat ion of endogenous peptides for presentation by class I molecules to cy totoxic T cells. Their possible role in the pathogenesis of insulin-de pendent diabetes mellitus (IDDM) has not been documented. In this stud y of Caucasian subjects, we have analyzed the polymorphisms of four ge nes within the HLA class II region (LMP2, LMP7, and HLA-DRB1 and -DQB1 ) in 198 unrelated IDDM patients and 192 normal controls ascertained f rom the southeastern United States. A genomic polymorphism of LMP7 was found strongly associated with IDDM, and the Arg/His-60 polymorphism in LMP2 was found associated with IDDM only in subjects containing an HLA DR4-DOB10302 haplotype. To determine whether the apparent associa tions between LMP genes and IDDM resulted from the strong linkage dise quilibria observed between LMP and HLA-DR/DQ genes, we compared LMP ge ne frequencies in extended LMP-HLA haplotypes derived from control and diabetic families. Our results suggest that LMP genes have independen t effects on TT)DM susceptibility.