title: Genetic polymorphisms in organic cation transporter 1 (OCT1) in Chinese and Japanese populations exhibit altered function.
abstract: 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.
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94158, USA.
authors.forename: Ligong
authors.initials: L
authors.lastname: Chen
authors.forename: Miho
authors.initials: M
authors.lastname: Takizawa
authors.forename: Eugene
authors.initials: E
authors.lastname: Chen
authors.forename: Avner
authors.initials: A
authors.lastname: Schlessinger
authors.forename: Julie
authors.initials: J
authors.lastname: Segenthelar
authors.forename: Ji Ha
authors.initials: JH
authors.lastname: Choi
authors.forename: Andej
authors.initials: A
authors.lastname: Sali
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.forename: Shinko
authors.initials: S
authors.lastname: Nakamura
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Iwamoto
authors.forename: Naoko
authors.initials: N
authors.lastname: Iwasaki
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Giacomini
mesh_terms: D000368:Aged; D001120:Arginine / Q000235:genetics; D001693:Biological Transport, Active; D019921:Biotinylation; D015153:Blotting, Western; D002460:Cell Line; D002681:China / Q000453:epidemiology; D004247:DNA / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D014644:Genetic Variation; D005838:Genotype; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism; D007564:Japan / Q000453:epidemiology; D007700:Kinetics; D008297:Male; D008687:Metformin / Q000378:metabolism; D008875:Middle Aged; D027702:Organic Cation Transporter 1 / Q000235:genetics* / Q000378:metabolism*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D016415:Sequence Alignment
chemical_list: D007004:Hypoglycemic Agents; D027702:Organic Cation Transporter 1; D049452:Green Fluorescent Proteins; D004247:DNA; D008687:Metformin; D001120:Arginine