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.

中文翻译：

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HLA-DRB1*16:02:01 和 SLC16A11 TCGTT 之间的上位性降低了西南美洲印第安人患 2 型糖尿病的几率

我们试图通过对所有研究参与者的高分辨率 HLA-DRB1 等位基因和 SLC16A11 进行基因分型来确定美国土著社区 2 型糖尿病的遗传/免疫因素，以测试他们患 2 型糖尿病的风险和/或保护作用。这些基数据集并执行 BMI 敏感性测试。我们将 SLC16A11 的风险保护单倍型 TCGTT 定义为具有三种基因型 SLC16A11*11、*12 和 *22 的双等位基因模型的等位基因“2”，其中等位基因“1”是野生型。两项早期发现均得到证实。在 BMI≥35 的同一逻辑模型中，DRB1*16:02:01 仍保持保护性，即 0.73，而 SLC16A11 从风险切换到保护 OR 分别 = 0.57 (*22) 和 0.78 (*12)；增加的交互作用项具有统计显着性（OR = 0.49，*12）。自举 (b=10,000) 交互作用统计功效为 0.4801，得出平均 OR = 0.43。敏感性分析表明，BMI 范围为 30-41 时，交互作用显着。为了研究上位性，我们使用 HLA-DRB1 分子的主要功能（肽结合和呈递）来搜索野生型和古代人类 SLC16A11 分子的整个 15mer 肽阵列，以寻找与风险和风险相关的强结合模式。 T2D 的保护。应用计算机结合算法表明，SLC16A11 D127G 的核心肽 FSAFASGLL 可能是调节 T2D 风险的关键，并对 T1D 具有潜在影响。