LINKAGE DISEQUILIBRIUM BETWEEN TAP2 VARIANTS AND HLA CLASS-II ALLELES- NO PRIMARY ASSOCIATION BETWEEN TAP2 VARIANTS AND INSULIN-DEPENDENT DIABETES-MELLITUS

The TAP1 and TAP2 genes, located in the HLA class II region, encode su bunits of a peptide transporter. Both genes display limited genetic va riability; four different nucleotide substitutions have been found in the TAP2 gene. Here studies on linkage disequilibrium between TAP2 var iants and HLA class II alleles are reported, in an attempt to evaluate whether TAP2 variants are associated with insulin-dependent diabetes mellitus (IDDM). As reported previously, a significant decrease of hom ozygosity for TAP2 alleles encoding alanine at residue 665 (665 Ala) a nd glutamine at 687 (687 Gln) paralleled by an increase in homozygosit y for TAP2 alleles encoding threonine at residue 665 (665 Thr) and a s top codon at 687 (687 Stop), was found in both Finnish and Norwegian I DDM patients compared to random controls. However, a strong linkage di sequilibrium between these TAP2 polymorphisms and given HLA-DR and -DQ genes was observed among healthy controls. The frequent 665 Thr and 6 87 Stop variants were in linkage disequilibrium both with the DR4-DQ8 and the DR3-DQ2 haplotypes, haplotypes which are strongly associated w ith IDDM. In contrast, the DR1-DQ5 and DR13-DQ6 (e.g. DQB10603) haplo types, which are decreased among IDDM patients, were associated with t he 665 Ala and 687 Gln variants.Thus,when DR- and DQ-matched patients and controls were compared, associations of the investigated TAP2 vari ants and IDDM were no longer detectable. These data, therefore, indica te that the associations previously found between certain TAP2 variant s and IDDM are secondary to a primary association between this disease and particular DQalphabeta heterodimers.