Exploring the Binding Polymorphism for HLA-A Alleles at the Ancient Human SLC16A11 Haplotype in Indigenous Americans with High Prevalence Type 2 Diabetes

The purpose of this work is to determine the relationship between the HLA-A alleles and SLC16A11 and estimate their risk/protection for type 2 diabetes mellitus (T2D) in a large indigenous American sample. The method uses binding prediction algorithms to identify risk 9mer peptides for the protein and develops polygenic statistical models that reflect the joint action of the two loci. The strength of peptide binding was estimated for the mutant form of the SLC16A11, T-C-G-T-T, with genotypes *11, *12, *22, risk allele = 2. Among the four polymorphic HLA-A alleles, binding polymorphisms were discovered for A*02:01 and A*02:06 at SLC16A11 missense site D127G. A binding polymorphism is defined as one in which the wildtype-consensus peptide has minimum binding while the mutation exhibits strong binding. For HLA-A*02:01 the binding double was [0.023, 0.487], respectively, while for A*02:06 it was [0.014, 0.207]. When A*02:01 genotypes were put in a logistic sensitivity analysis in < BMI kg/m2 strata 25-45, no significant associations were observed. When SLC16A11 genotypes were added, with interaction, the odds ratios for risk allele 2 genotypes were significantly increased. A new, polygenic logistic sensitivity analysis was created that generalized the risk alleles for the two loci (A*02:01, A*02:06, and T-C-G-T-T) with five risk allele (RA) categories, 4, 3, 2, 1, 0. The most significant stratum was < BMI 31 for risk categories 4 (OR=3.33, statistical power=0.819), 3 (2.64, 0.933), and 2 (1.91, 0.722). A statistically significant weighted linear regression across RA categories was OR = 0.583RA + 0.811 with R2 = 0.975. The binding polymorphisms, polygenic analysis, linear regressions, and power estimates lead to the conclusion that HLA peptide presenting molecules need a tripartite statistical model to test associations: disease, HLA allele, and target protein peptide.