FAMILY STUDY OF LINKAGE DISEQUILIBRIUM BETWEEN TAP2 TRANSPORTER AND HLA CLASS-II GENES - ABSENCE OF TAP2 CONTRIBUTION TO ASSOCIATION WITH INSULIN-DEPENDENT DIABETES-MELLITUS

The polymorphic TAP1 and TAP2 genes encode a transporter protein requi red for delivery of cytosolic peptides to class I molecules in the end oplasmic reticulum. Associations have been observed between TAP2 allel es and predisposition to autoimmune diseases such as IDDM but their in terpretation has been complicated by the existence of LD between TAP2 and HLA class II loci, and conclusions are still contradictory. In ord er to precisely define LD on class II haplotypes, we performed an exte nsive familial analysis. A total of 466 individuals from 55 normal fam ilies and 49 IDDM multiplex families was studied, providing informatio n on 420 independent haplotypes. The IDDM-predisposing DRB103 and DRB 104 alleles were in strong negative LD with TAP2-B (Delta = -0.035 an d -0.034, respectively), and positive LD with TAP2-A (Delta = -0.055 a nd +0.012). Positive LD was also found between TAP2-B and DRB101 and TAP2-C and DRB111 alleles. We then addressed the question of whether TAP2 is an independent additional IDDM-protective or predisposing gene tic factor. No TAP2 effect was evidenced when considering DRB103 and/ or 04 patients. A decreased TAP2-B phenotype frequency was observed in DRB103- and DRB1*04-negative IDDM patients compared with DRB1*03- an d DRB1O4-negative normal controls (38.6% vs 63%, p(c) < 0.05), but wa s probably related to a combination of different weak LD between DRB1 and TAP2 alleles. It thus appears that there is no primary association between TAP2 alleles and IDDM. However, TAP polymorphism may allow us to define particular extended HLA haplotypes involved in susceptibili ty to autoimmune diseases.