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

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.

MR1 encompasses at least six allele groups with coding region alterations.

Unlike classical HLA class I genes, MR1 is assumed to have limited polymorphic positions. We developed a MR1 specific PCR assay and sequenced 56 DNA samples from cells with a diverse set of HLA genotypes. In this relatively small panel we found six allele groups encoding for different MR1 proteins. The two most frequent allele groups found in this panel had a frequency of 71% (MR1*01) and 25% (MR1*02), respectively. Moreover, the panel contained many intronic SNPs and silent variants, with individual samples containing up to 15 heterozygous positions. The data presented here is consistent with marked variation in MR1.