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Supplementary_1602_slc16a11_Materials_03_20_2024.pdf (909.5 kB)

Epistasis Between HLA-DRB1*16:02:01 and SLC16A11 T-C-G-T-T Reduces Odds for Type 2 Diabetes in Southwest American Indians

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posted on 2024-03-26, 18:31 authored by Robert C. Williams, Robert L. Hanson, Bjoern Peters, Kendall Kearns, William C. Knowler, Clifton Bogardus, Leslie J. Baier

We sought to identify genetic/immunologic contributors of type 2 diabetes in an indigenous American community by genotyping all study participants for both high resolution HLA-DRB1 alleles and SLC16A11 to test their risk and/or protection for T2D. These genes were selected based on independent reports that HLA-DRB1*16:02:01 is protective for T2D and that SLC16A11 associates with T2D in individuals with BMI<35kg/m2, and here test the interaction of the two loci with a more complete dataset and perform a BMI sensitivity test. We define the risk-protection haplotype of SLC16A11, T-C-G-T-T, as allele “2” of a di-allelic genetic model with three genotypes, SLC16A11*11, *12, and *22, where allele “1” is the wildtype. Both earlier findings were confirmed. Together in the same logistic model with BMI≥35, DRB1*16:02:01 remains protective, 0.73, while SLC16A11 switches from risk to protection OR = 0.57 (*22) and 0.78 (*12), respectively; an added interaction term was statistically significant (OR = 0.49 with *12). Bootstrapped (b=10,000) statistical power of interaction, 0.4801, yielded mean OR = 0.43. Sensitivity analysis demonstrated the interaction significant in BMI range 30-41. To investigate the epistasis we used the primary function of the HLA-DRB1 molecule, peptide binding and presentation, to search the entire array of 15mer peptides for both the wildtype and ancient human SLC16A11 molecules for a pattern of strong binding that was associated with risk and protection for T2D. Applying computer binding algorithms suggests the core peptide at SLC16A11 D127G, FSAFASGLL, might be key for moderating risk for T2D with potential implications for T1D.

Funding

This research was supported in part by the Intramural Research Program of the NIH, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

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