TAP2 association with insulin-dependent diabetes mellitus is secondary to HLA-DQB1

IDDM is known to be associated with genes of HLA complex, particularly alleles of HLA-DQ. The 40-kb TAP gene complex is located approximately 150 kb centrometric to the DQB1 locus. The TAP1-TAP2 protein heterodimer is required for normal expression levels of class I, molecules on the surface of cells. While present evidence implicates HLA-DQ as the major susceptibility locus in IDDM, as class I expression apparently plays a role in the progression of disease, the possibility exists that the association attributed to HLA-DQ is in fact due to an association with the TAP genes. Several studies have concluded that the alleles of TAP1 are not significantly associated with IDDM; this report concentrates on the more telomeric TAP2 locus. During this investigation, six previously described TAP2 alleles were identified in 208 normal Caucasians and 241 Caucasian diabetics. Sequence analysis of cDNA clones identified a seventh allele of TAP2, TAP2*F, which contains an arginine-to-cystine interchange at amino acid position 651. Overall, our results indicate only a modest association of IDDM with TAP2; however, the newly described TAP2*F allele was found to be significantly increased in a modest subset of our large diabetic population. These data, generated from the same population of controls and diabetics we previously studied at all other relevant MHC loci, provide additional evidence that the HLA susceptibility to IDDM maps to HLA-DQ.