Genetic Polymorphisms in Organic Cation Transporter 1 (OCT1) in Chinese and Japanese Populations Exhibit Altered Function
Genetic Polymorphisms in Organic Cation Transporter 1 (OCT1) in Chinese and Japanese Populations Exhibit Altered Function
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DOI：
10.1124/jpet.110.170159
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发表时间：
2010-10-10
影响因子：
3.5
通讯作者：
Giacomini, Kathleen M.
中科院分区：
文献类型：
--
作者：
Chen, Ligong;Takizawa, Miho;Giacomini, Kathleen M.
有机阳离子转运蛋白 1（OCT1；SLC22A1）似乎在广泛使用的抗糖尿病药物二甲双胍的功效和处置中发挥着重要作用。 OCT1 的遗传变异主要在欧洲人群中被发现。二甲双胍越来越多地在 2 型糖尿病 (T2D) 发病率上升的亚洲人群中使用。本研究的目的是鉴定中国和日本人群中 OCT1 的遗传变异，这可能会调节对二甲双胍的反应。我们使用了千人基因组计划（中国和日本）的最新数据，并对来自日本 2 型糖尿病患者的 66 个 DNA 样本中选定的 OCT1 扩增子进行了直接测序。总共鉴定出六个非同义变体。其中三个（Q97K、P117L 和 R206C）之前尚未进行功能表征，等位基因频率分别为 0.017、0.023 和 0.008。相对于 OCT1 参考，表达 Q97K、P117L 和 R206C 的细胞中二甲双胍的摄取显着减少（Q97K、P117L 和 R206C 分别为 62 +/- 4.3、55 +/- 6.8 和 22 +/- 1.5%）。动力学研究表明，P117L 和 R206C 表现出 V-max 降低，而 Q97K 表现出 K-m 增加。绿色荧光蛋白 (GFP) 标记的 Q97K 和 P117L 变体定位于质膜，而 GFP 标记的 R206C 主要保留在内质网中。用不同氨基酸替换高度保守的 R206 可调节转运蛋白的亚细胞定位和功能。这项研究表明，中国和日本人群中 OCT1 的非同义变异可能会影响对二甲双胍的差异反应。
Organic cation transporter 1 (OCT1; SLC22A1) seems to play a role in the efficacy and disposition of the widely used antidiabetic drug metformin. Genetic variants in OCT1 have been identified largely in European populations. Metformin is increasingly being used in Asian populations where the incidence of type 2 diabetes (T2D) is on the rise. The goal of this study is to identify genetic variants of OCT1 in Chinese and Japanese populations, which may potentially modulate response to metformin. We used recent data from the 1000 Genomes Project (Chinese and Japanese) and direct sequencing of selected amplicons of OCT1 in 66 DNA samples from Japanese patients with T2D. A total of six nonsynonymous variants were identified. Three of them (Q97K, P117L, and R206C) had not been functionally characterized previously and had allele frequencies of 0.017, 0.023 and 0.008, respectively. The uptake of metformin in cells expressing Q97K, P117L, and R206C was significantly reduced relative to the OCT1 reference (62 +/- 4.3, 55 +/- 6.8, and 22 +/- 1.5% for Q97K, P117L, and R206C, respectively). Kinetic studies indicated that P117L and R206C exhibited a reduced V-max, whereas Q97K showed an increased K-m. The green fluorescent protein (GFP)-tagged Q97K and P117L variants localized to the plasma membrane, whereas the GFP-tagged R206C was retained mainly in the endoplasmic reticulum. Replacement of the highly conserved R206 with different amino acids modulated the subcellular localization and function of the transporter. This study suggests that nonsynonymous variants of OCT1 in Chinese and Japanese populations may affect the differential response to metformin.