Supplementary Material for: Transporters, <b><i>TBC1D4</i></b>, and <b><i>ARID5B</i></b> Variants to Explain Glycated Hemoglobin Variability in Patients with Type 2 Diabetes
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<b><i>Introduction:</i></b> Genetic variants could aid in predicting antidiabetic drug response by associating them with markers of glucose control, such as glycated hemoglobin (HbA1c). However, pharmacogenetic implementation for antidiabetics is still under development, as the list of actionable markers is being populated and validated. This study explores potential associations between genetic variants and plasma levels of HbA1c in 100 patients under treatment with metformin. <b><i>Methods:</i></b> HbA1c was measured in a clinical chemistry analyzer (Roche), genotyping was performed in an Illumina-GSA array and data were analyzed using PLINK. Association and prediction models were developed using R and a 10-fold cross-validation approach. <b><i>Results:</i></b> We identified genetic variants on <i>SLC47A1, SLC28A1, ABCG2, TBC1D4,</i> and <i>ARID5B</i> that can explain up to 55% of the interindividual variability of HbA1c plasma levels in diabetic patients under treatment. Variants on <i>SLC47A1</i>, <i>SLC28A1</i>, and <i>ABCG2</i> likely impact the pharmacokinetics (PK) of metformin, while the role of the two latter can be related to insulin resistance and regulation of adipogenesis. <b><i>Conclusions:</i></b> Our results confirm previous genetic associations and point to previously unassociated gene variants for metformin PK and glucose control.
**引言**：遗传变异可通过与血糖控制标志物（如糖化血红蛋白（glycated hemoglobin, HbA1c)）关联，助力预测抗糖尿病药物的响应效果。然而，抗糖尿病药物的药物遗传学应用仍处于研发阶段，其可操作标志物列表尚在扩充与验证中。本研究探究了100名接受二甲双胍（metformin）治疗的患者中，遗传变异与血浆糖化血红蛋白水平之间的潜在关联。**方法**：采用罗氏（Roche）临床化学分析仪检测糖化血红蛋白水平，通过Illumina-GSA基因芯片完成基因分型，并使用PLINK软件对数据进行分析。关联分析与预测模型基于R语言构建，并采用10折交叉验证（10-fold cross-validation）方法。**结果**：本研究在SLC47A1、SLC28A1、ABCG2、TBC1D4以及ARID5B基因上发现了可解释接受治疗的糖尿病患者血浆糖化血红蛋白水平个体间差异高达55%的遗传变异。其中，SLC47A1、SLC28A1与ABCG2上的变异可能影响二甲双胍的药物代动力学（pharmacokinetics, PK），而后两个基因的变异则可能与胰岛素抵抗及脂肪生成调控相关。**结论**：本研究结果验证了此前已报道的遗传关联，并指出了与二甲双胍药物代动力学及血糖控制相关的、此前未被发现的基因变异。
