The HLA DQB1(*)0502 allele is neutrally associated with insulin-dependent diabetes mellitus in the Sardinian population

In the Sardinian population a very high incidence of insulin-dependent diabetes mellitus (IDDM) and the lack of HLA-DR2 protective effect due to the high frequency of the A2, Cw7, B17, 3F31, DR2, DQw1 extended haplotype has been reported. This haplotype, carrying a Serine at position 57 of the DQB1(*)0502 allele, has been previously reported to be underrepresented in patients when compared to controls. In order to provide an explanation for this finding, we defined by RFLP analysis the HLA haplotype of 45 Sardinian IDDM patients and 49 controls. All DR-2DQw1 subjects were molecularly characterized at the HLA DQA and DQB loci. All DR2-positive patients and the vast majority of the DR2-positive controls had the DQB1(*)0502 allele at the DR2-1inked DQB1 locus, with no statistically significant difference between the two groups. All DQA1 genes were the ones expected, with only two exceptions. Nine out of 10 of the DR2-positive patients were compound heterozygotes for DQB1(*)0201/DQB1(*)0502 alleles: only this allele combination was significantly increased (p<0.0003). Our data suggests that a) the DQB1(*)0502 allele is neutral for IDDM development and b) the susceptibility to IDDM in our DR2-positive patients is related to the compound hetrozygous state between the neutral DQA1(*)0102/DQB1(*)0502 and the susceptibility DQA1(*)0501/DQB1(*)0201 alleles.