Family-based association of HLA-DRB1 and DQB1 alleles and haplotypes in a group of Iranian Type 1 diabetes children.

ABSTRACT

This family-based study was conducted in a group of Iranians with Type 1 diabetes (T1D) to investigate the transmission from parents of risk and non-risk HLA alleles and haplotypes, and to estimate the genetic risk score for this disease within this population. A total of 240 T1D subjects including 111 parent-child trios (111 children with T1D, 133 siblings, and 222 parents) and 330 ethnically matched healthy individuals were recruited. High-resolution HLA typing for DRB1/DQB1 loci was performed for all study subjects (n = 925) using polymerase chain reaction-sequence-specific oligonucleotide probe method. The highest predisposing effect on developing T1D was conferred by the following haplotypes both in all subjects and in probands compared to controls DRB1*0405-DQB1*0302 (Pc = 2.97e-06 and Pc = 6.04e-10, respectively), DRB1*0402-DQB1*0302 (Pc = 5.94e-17 and Pc = 3.86e-09, respectively), and DRB1*0301-DQB1*0201 (Pc = 8.26e-29 and Pc = 6.56e-16, respectively). Conversely, the major protective haplotypes included DRB1*1301-DQB1*0603 (Pc = 6.99e-08), DRB1*1501-DQB1*0602 (Pc = 2.97e-06) in the cases versus controls. Also, DRB1*0301-DQB1*0201/DRB1*0402|05-DQB1*0302 and DRB1*0301-DQB1*0201/DRB1*0301-DQB1*0201 diplotypes conferred the highest predisposing effect in the cases (Pc = 8.65e-17 and Pc = 6.26e-08, respectively) and in probands (Pc = 5.4e-15 and Pc = 0.001, respectively) compared to controls. Transmission disequilibrium test showed that the highest risk was conferred by DRB1*0402-DQB1*0302 (Pc = 3.26e-05) and DRB1*0301-DQB1*0201 (Pc = 1.78e-12) haplotypes and the highest protection by DRB1*1401-DQB1*0503 (Pc = 8.66e-05), DRB1*1501-DQB1*0602 (Pc = 0.002), and DRB1*1101-DQB1*0301 (Pc = 0.0003) haplotypes. Based on logistic regression analysis, carriage of risk haplotypes increased the risk of T1D development 24.5 times in the Iranian population (p = 5.61e-13). Also, receiver operating characteristic curve analysis revealed a high predictive power of those risk haplotypes in discrimination of susceptible from healthy individuals (area under curve 0.88, p = 5.5e-32). Our study highlights the potential utility of genetic risk assessment based on HLA diplotypes for predicting T1D risk in individuals, particularly among family members of affected children in our population.