The influence of the HLA-DRB, HLA-DQB and polymorphic positions of the HLA-DRβ1 and HLA-DQβ1 molecules on risk of Iranian type 1 diabetes mellitus patients.

Type 1 Diabetes mellitus (T1D) is an autoimmune and multifactorial disease. HLA-DRB1 and DQB1 loci have the strongest association with T1D. This study aimed at investigating (i) susceptibility or protection of alleles, genotypes and haplotypes of HLA-DRB1 and DQB1 loci; and (ii) highly polymorphic amino acid residues of HLA-DRβ1 and DQβ1 in 105 Iranian T1D patients and 100 controls. The results indicated that DRB104:01, 03:01, DQB103:02, 02:01 alleles, DRB103:01/04:01, 03:01/13:03, DQB102:01/03:02 genotypes, DRB104:01-DQB103:02, DRB103:01-DQB102:01, DRB107:01-DQB103:03 haplotypes had positive association with T1D. In contrast, HLA-DRB115:01, 13:01, DQB103:01, 06:01 alleles, DRB111:01/15:01, DQB103:01/06:01, 03:01/05:01 genotypes and DRB115:01-DQB106:01, DRB111:01-DQB103:01 haplotypes had negative association with T1D. Analysis of amino acid sequence of HLA-DRβ1 and DQβ1 revealed that DRβ1(Lys71+) and DQβ1(Asp57-) were significantly more frequent in patients than in controls and had a positive effect in the development of T1D. Haplotype analysis demonstrated that HLA-DRB1(Lys71+) allele provided major susceptibility for T1D, and DQβ1(Asp57-) had an additive effect. We designed an allele-specific primer to develop an easy, quick and cost-benefit method to detect the DRβ1(Lys71+) . This method can identify all 114 DRB1 alleles encoding DRβ1(Lys71+) by three PCR reactions. The PcPPV and PcNPV were also calculated to determine the impact of HLA genotype testing at amino acid positions. It showed that the DRβ1(Lys71+/+) genotype carrier had 1% absolute risk of developing T1D.