Complete HLA genotyping of type 1 diabetes patients and controls from Mali reveals both expected and novel disease associations

Abstract

HLA genotyping was performed on 99 type 1 diabetes (T1D) patients and 200 controls from Mali. Next‐generation sequencing of the classical HLA‐A, ‐B, ‐C, ‐DRB1, ‐DRB3, ‐DRB4, ‐DRB5, ‐DQA1, ‐DQB1, ‐DPA1, and ‐DPB1 loci revealed strong T1D association for all loci except HLA‐C and ‐DPA1. Class II association is stronger than class I association, with most observed associations predisposing or protective as expected based on previous studies. For example, HLA‐DRB1*03:01, HLA‐DRB1*09:01, and HLA‐DRB1*04:05 predispose for T1D, whereas HLA‐DRB1*15:03 is protective. HLA‐DPB1*04:02 (OR = 12.73, p = 2.92 × 10−05) and HLA‐B*27:05 (OR = 21.36, p = 3.72 × 10−05) appear highly predisposing, although previous studies involving multiple populations have reported HLA‐DPB1*04:02 as T1D‐protective and HLA‐B*27:05 as neutral. This result may reflect the linkage disequilibrium between alleles on the extended HLA‐A*24:02~HLA‐B*27:05~HLA‐C*02:02~HLA‐DRB1*04:05~HLA‐DRB4*01:03~HLA‐DQB1*02:02~HLA‐DQA1*02:01~HLA‐DPB1*04:02~HLA‐DPA1*01:03 haplotype in this population rather than an effect of either allele itself. Individual amino acid (AA) analyses are consistent with most T1D association attributable to HLA class II rather than class I in this data set. AA‐level analyses reveal previously undescribed differences of the HLA‐C locus from the HLA‐A and HLA‐B loci, with more polymorphic positions, spanning a larger portion of the gene. This may reflect additional mechanisms for HLA‐C to influence T1D risk, for example, through expression differences or through its role as the dominant ligand for killer cell immunoglobulin‐like receptors (KIR). Comparison of these data to those from larger studies and on other populations may facilitate T1D prediction and help elucidate elusive mechanisms of how HLA contributes to T1D risk and autoimmunity.