Genomic evaluation of HLA‐DR3+ haplotypes associated with type 1 diabetes

• DOI: 10.1111/nyas.12019
• Publication Date: 2013-02-06T20:17:31Z
• Authors: Neeraj Kumar; Gurvinder Kaur; Nikhil Tandon; Uma Kanga; Narinder K. Mehra
• Keywords: 0303 health sciences; 03 medical and health sciences; Diabetes Mellitus, Type 1; HLA-DR3 Antigen; HLA-A Antigens; Haplotypes; Risk Factors; Humans; India; Genomics

We have defined three sets of HLA‐DR3+ haplotypes that provide maximum risk of type 1 disease development in Indians: (1) a diverse array of B8‐DR3 haplotypes, (2) A33‐B58‐DR3 haplotype, and (3) A2‐B50‐DR3 occurring most predominantly in this population. Further analysis has revealed extensive diversity in B8‐DR3 haplotypes, particularly at the HLA‐A locus, in contrast to the single fixed HLA‐A1‐B8‐DR3 haplotype (generally referred to as AH8.1) reported in Caucasians. However, the classical AH8.1 haplotype was rare and differed from the Caucasian counterpart at multiple loci. In our study, HLA‐A26‐B8‐DR3 (AH8.2) was the most common B8‐DR3 haplotype constituting >50% of the total B8‐DR3 haplotypes. Further, A2‐B8‐DR3 contributed the maximum risk (RR = 48.7) of type 1 diabetes, followed by A2‐B50‐DR3 (RR = 9.4), A33‐B58‐DR3 (RR = 6.6), A24‐B8‐DR3 (RR = 4.5), and A26‐B8‐DR3 (RR = 4.2). Despite several differences, the disease‐associated haplotypes in Indian and Caucasian populations share a frozen DR3‐DQ2 block, suggesting a common ancestor from which multiple haplotypes evolved independently.