Aim: Genetic risk for type 1 diabetes (T1D) has been reported for all classical HLA loci. Genes encoding class II DR and DQ antigens confer the strongest risk, with other loci contributing less to susceptibility. HLA-C frequently exhibits weak or no association with T1D susceptibility; reports of associated alleles show little consistency among populations. The aim of this study was to examine the basis of HLA-C-related susceptibility to T1D and reveal potential mechanistic differences between HLA-C-associated T1D risk and risk conferred by other classical HLA-loci.
Methods: Data for these analyses were from the Type 1 Diabetes Genetics Consortium (T1DGC) and from sample sets obtained in Mali, Pakistan, Bangladesh, and Azerbaijan, genotyped in collaboration with the Life for a Child (LFAC) Programme. HLA genotyping methods included PCR-SSOP (T1DGC samples) or whole gene sequencing (LFAC samples). Allele and amino acid analyses were performed with BIGDAWG version 3.0.6.
Results: Data from multiple populations were examined. Data from subjects of European ancestry (EUR) and from subjects of African American ancestry (AA) were from the T1DGC study. Significance for overall HLA-C locus association with T1D ranged from not significant (Bangladesh, Mali) to weak (Azerbaijan, p=0.002) to strong (Pakistan p=3 x 10-5, EUR and AA, p < 10-6). Few HLA-C alleles demonstrated T1D association, and those were rarely shared among populations. By contrast, examination of amino acid residue positions in these populations revealed associations in exon 5 in positions encoding residues 300-309, which encodes a peptide connecting the surface portion of the antigen to the transmembrane region. Position 309 has been reported to affect the innate immune response.
Conclusion: Susceptibility to T1D conferred by the HLA-C locus appears to differ from the traditional antigen presentation mechanism attributed to other classical HLA loci; HLA-C-associated T1D risk spans more of the gene rather than just the portions that encode the peptide-binding groove. Based on analyses of individual amino acid variants, the region of HLA-C that connects the extracellular antigen to the membrane may contribute to T1D risk. Structural and functional examination is needed to address the mechanism of HLA-C associated T1D risk and to explore whether HLA-C interaction with the innate immune system plays a role.
