Association of HLA class II alleles and CTLA-4 polymorphism with type 1 diabetes.

Type-1 diabetes mellitus (T1DM) is a progressive complex autoimmune disease in which combinations of environmental as well as genetic factors contribute to T-cell mediated destruction of insulin-secreting β-cells of the pancreas. HLA class II alleles on chromosome 6p21 [insulin dependent diabetes mellitus 1 (IDDM1)],especially DR and DQ,show strong association with T1DM. In addition,several studies have suggested that polymorphisms in the CTLA-4 gene (IDDM12) on chromosome 2q33 form part of the genetic susceptibility for type 1 diabetes. The aim of this study was to analyze HLA alleles of the DQB1 and DRB1 genes using polymerase chain reaction using sequence specific primers (PCR-SSP) technique and to investigate the association of the A49G CTLA-4 polymorphism using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis in Lebanese T1DM patients. The study was conducted on 39 Lebanese T1DM patients. Results of HLA typing showed an increased frequency of the HLA-DQB1FNx010201,HLA-DQB1FNx010302,HLA-DRB1FNx010301 and HLA-DRB1FNx010401 alleles,suggesting risk association and thus can be considered as susceptibility alleles. On the other hand,strong protection against the disease was conferred by the HLA-DRB1FNx01110101,HLA-DQB1FNx010301 and HLADQB1FNx010601 alleles. RFLP analysis of the A49G polymorphism showed a significant increase in the G allele and GG genotype frequencies in patients,suggesting that CTLA-4 may be considered as a susceptibility gene for the development of T1DM in the Lebanese population. Analysis of the two polymorphisms showed no detectable association between the two genes. However,a significant negative association of the G allele with the DQB1FNx010201 allele was observed. This might indicate that the two genetic risk factors,namely HLA and CTLA-4,act independently of each other with no additive effect.