Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ.
La Jolla Institute for Immunology, La Jolla, CA.
Diabetes. 2024 Jun 1;73(6):1002-1011. doi: 10.2337/db23-0925.
We sought to identify genetic/immunologic contributors of type 2 diabetes (T2D) 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-DRB116:02:01 is protective for T2D and that SLC16A11 associates with T2D in individuals with BMI <35 kg/m2. Here, we test the interaction of the two loci with a more complete data set and perform a BMI sensitivity test. We defined the risk protection haplotype of SLC16A11, T-C-G-T-T, as allele 2 of a diallelic genetic model with three genotypes, SLC16A1111, *12, and 22, where allele 1 is the wild type. Both earlier findings were confirmed. Together in the same logistic model with BMI ≥35 kg/m2, DRB116:02:01 remains protective (odds ratio [OR] 0.73), while SLC16A11 switches from risk to protection (OR 0.57 [*22] and 0.78 [*12]); an added interaction term was statistically significant (OR 0.49 [*12]). Bootstrapped (b = 10,000) statistical power of interaction, 0.4801, yielded a mean OR of 0.43. Sensitivity analysis demonstrated that the interaction is significant in the BMI range of 30-41 kg/m2. To investigate the epistasis, we used the primary function of the HLA-DRB1 molecule, peptide binding and presentation, to search the entire array of 15-mer peptides for both the wild-type and ancient human SLC16A11 molecules for a pattern of strong binding that was associated with risk and protection for T2D. Applying computer binding algorithms suggested that the core peptide at SLC16A11 D127G, FSAFASGLL, might be key for moderating risk for T2D with potential implications for type 1 diabetes.
我们通过对所有研究参与者进行高分辨率 HLA-DRB1 等位基因和 SLC16A11 分型，以鉴定 2 型糖尿病 (T2D) 的遗传/免疫贡献者，从而检测这些基因对 T2D 的风险和/或保护作用。选择这些基因是基于独立报告，即 HLA-DRB116:02:01 对 T2D 具有保护作用，而 SLC16A11 与 BMI<35kg/m2 的个体的 T2D 相关。在这里，我们使用更完整的数据集测试了两个位点的相互作用，并进行了 BMI 敏感性测试。我们将 SLC16A11 的风险保护单倍型 T-C-G-T-T 定义为二态遗传模型的等位基因 2，该模型有三个基因型，SLC16A1111、12 和22，其中等位基因 1 是野生型。这两个早期发现都得到了证实。在包含 BMI≥35kg/m2 的相同逻辑模型中，DRB1*16:02:01 仍然具有保护作用（比值比 [OR]0.73），而 SLC16A11 则从风险变为保护（OR0.57[*22]和 0.78[*12]）；一个额外的相互作用项具有统计学意义（OR0.49[*12]）。基于 10,000 次自举（b）的交互作用统计功效为 0.4801，产生的平均 OR 为 0.43。敏感性分析表明，在 BMI 为 30-41kg/m2 的范围内，这种相互作用具有统计学意义。为了研究上位性，我们使用 HLA-DRB1 分子的主要功能，即肽结合和呈递，在野生型和古老的人类 SLC16A11 分子中搜索整个 15 肽序列，寻找与 T2D 风险和保护相关的强结合模式。应用计算机结合算法表明，SLC16A11 D127G 处的核心肽 FSAFASGLL 可能是调节 T2D 风险的关键，这可能对 1 型糖尿病有潜在影响。
