Abstract

Several pharmacogenetics studies have identified an association between a greater metformin-dependent reduction in HbA1c levels and the minor A allele at rs2289669 in intron 10 of SLC47A1, encoding multidrug and toxin extrusion 1 (MATE1), a presumed metformin transporter. It is currently unknown if the rs2289669 locus is a cis-eQTL, which would validate its role as predictor of metformin efficacy. We looked at association between common genetic variants in the SLC47A1 gene region and HbA1c reduction after metformin treatment using locus-wise meta-analysis from the MetGen consortium. CRISPR-Cas9 was applied to perform allele editing of, or genomic deletion around, rs2289669 and of the closely linked rs8065082 in HepG2 cells. The genome-edited cells were evaluated for SLC47A1 expression and splicing. None of the common variants including rs2289669 showed significant association with metformin response. Genomic editing of either rs2289669 or rs8065082 did not alter SLC47A1 expression or splicing. Experimental and in silico analyses show that the rs2289669-containing haploblock does not appear to carry genetic variants that could explain its previously reported association with metformin efficacy.

中文翻译：

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SLC47A1 中二甲双胍疗效相关基因变异的基因组编辑不会改变 SLC47A1 的表达

摘要

几项药物遗传学研究已确定 HbA1c 水平的二甲双胍依赖性降低与 SLC47A1 内含子 10 中rs2289669的次要 A 等位基因之间的关联，编码多药和毒素排出 1 (MATE1)，一种假定的二甲双胍转运蛋白。目前尚不清楚 rs2289669 基因座是否为 cis-eQTL，这将验证其作为二甲双胍疗效预测因子的作用。我们使用 MetGen 联盟的位点荟萃分析研究了SLC47A1基因区域中常见遗传变异与二甲双胍治疗后 HbA1c 降低之间的关联。CRISPR-Cas9 用于对 HepG2 细胞中的 rs2289669 和紧密相连的 rs8065082 进行等位基因编辑或基因组缺失。对基因组编辑的细胞进行了评估SLC47A1表达和剪接。包括 rs2289669 在内的常见变体均未显示出与二甲双胍反应的显着相关性。rs2289669 或 rs8065082 的基因组编辑不会改变SLC47A1 的表达或剪接。实验和计算机分析表明，含有 rs2289669 的单倍块似乎没有携带可以解释其先前报道的与二甲双胍功效相关的遗传变异。