Pharmacogenomics Laboratory, Instituto Nacional de Medicina Genómica, CDMX, Mexico.
Genetics Laboratory, Vitagénesis, Monterrey, Mexico.
Pharmacology. 2021;106(11-12):588-596. doi: 10.1159/000517462. Epub 2021 Jul 15.
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.
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.
We identified genetic variants on SLC47A1, SLC28A1, ABCG2, TBC1D4, and ARID5B that can explain up to 55% of the interindividual variability of HbA1c plasma levels in diabetic patients under treatment. Variants on SLC47A1, SLC28A1, and ABCG2 likely impact the pharmacokinetics (PK) of metformin, while the role of the two latter can be related to insulin resistance and regulation of adipogenesis.
Our results confirm previous genetic associations and point to previously unassociated gene variants for metformin PK and glucose control.
通过将遗传变异与血糖控制标志物（如糖化血红蛋白 [HbA1c]）相关联，遗传变异可以帮助预测抗糖尿病药物的反应。然而，由于可操作标志物的清单正在不断充实和验证，抗糖尿病药物的遗传药理学实施仍在不断发展中。本研究探讨了 100 名接受二甲双胍治疗的患者中遗传变异与 HbA1c 血浆水平之间的潜在关联。
在临床化学分析仪（罗氏）中测量 HbA1c，在 Illumina-GSA 阵列中进行基因分型，并使用 PLINK 进行数据分析。使用 R 和 10 倍交叉验证方法开发关联和预测模型。
我们在 SLC47A1、SLC28A1、ABCG2、TBC1D4 和 ARID5B 上鉴定出了遗传变异，这些变异可以解释接受治疗的糖尿病患者 HbA1c 血浆水平个体间变异性的高达 55%。SLC47A1、SLC28A1 和 ABCG2 上的变异可能影响二甲双胍的药代动力学（PK），而后两者的作用可能与胰岛素抵抗和脂肪生成调节有关。
我们的结果证实了先前的遗传关联，并指出了与二甲双胍 PK 和血糖控制相关的先前未关联的基因变异。
