title: Variants in Pharmacokinetic Transporters and Glycemic Response to Metformin: A Metgen Meta-Analysis.
abstract: Therapeutic response to metformin, a first-line drug for type 2 diabetes (T2D), is highly variable, in part likely due to genetic factors. To date, metformin pharmacogenetic studies have mainly focused on the impact of variants in metformin transporter genes, with inconsistent results. To clarify the significance of these variants in glycemic response to metformin in T2D, we performed a large-scale meta-analysis across the cohorts of the Metformin Genetics Consortium (MetGen). Nine candidate polymorphisms in five transporter genes (organic cation transporter [OCT]1, OCT2, multidrug and toxin extrusion transporter [MATE]1, MATE2-K, and OCTN1) were analyzed in up to 7,968 individuals. None of the variants showed a significant effect on metformin response in the primary analysis, or in the exploratory secondary analyses, when patients were stratified according to possible confounding genotypes or prescribed a daily dose of metformin. Our results suggest that candidate transporter gene variants have little contribution to variability in glycemic response to metformin in T2D.
authors.affiliation: Department of Biochemistry and Clinical Analysis, Faculty of Pharmacy, University of Sarajevo, Sarajevo, Bosnia and Herzegovina.|Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee, UK.
authors.forename: T
authors.initials: T
authors.lastname: Dujic
authors.affiliation: Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee, UK.
authors.forename: K
authors.initials: K
authors.lastname: Zhou
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.
authors.forename: S W
authors.initials: SW
authors.lastname: Yee
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: N
authors.initials: N
authors.lastname: van Leeuwen
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.|Inspectorate of Healthcare, Utrecht, The Netherlands.
authors.forename: C E
authors.initials: CE
authors.lastname: de Keyser
authors.affiliation: Department of Internal Medicine 4, Faculty of Medicine, Šafárik University, Košice, Slovakia.|Pasteur University Hospital, Košice, Slovakia.
authors.forename: M
authors.initials: M
authors.lastname: Javorský
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.
authors.forename: S
authors.initials: S
authors.lastname: Goswami
authors.affiliation: Latvian Biomedical Research and Study Centre, Riga, Latvia.
authors.forename: L
authors.initials: L
authors.lastname: Zaharenko
authors.affiliation: Department of Clinical Chemistry and Pharmacology, Odense University Hospital, Odense, Denmark.
authors.forename: M M
authors.initials: MM
authors.lastname: Hougaard Christensen
authors.affiliation: Treant Zorggroep, Location Bethesda, Hoogeveen, The Netherlands.|Bethesda Diabetes Research Centre, Hoogeveen, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Out
authors.affiliation: Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee, UK.
authors.forename: R
authors.initials: R
authors.lastname: Tavendale
authors.affiliation: Core for Genomic Medicine, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kubo
authors.affiliation: Division of Research, Kaiser Permanente Northern California, Oakland, California, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Hedderson
authors.affiliation: Department of General Practice, EMGO+ Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: A A
authors.initials: AA
authors.lastname: van der Heijden
authors.affiliation: Department of Medical Biology, Faculty of Medicine, Šafárik University, Košice, Slovakia.
authors.forename: L
authors.initials: L
authors.lastname: Klimčáková
authors.affiliation: Latvian Biomedical Research and Study Centre, Riga, Latvia.
authors.forename: V
authors.initials: V
authors.lastname: Pirags
authors.affiliation: Treant Zorggroep, Location Bethesda, Hoogeveen, The Netherlands.|Bethesda Diabetes Research Centre, Hoogeveen, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Kooy
authors.affiliation: Department of Public Health, Clinical Pharmacology and Pharmacy, University of Southern Denmark, Odense, Denmark.
authors.forename: K
authors.initials: K
authors.lastname: Brøsen
authors.affiliation: Latvian Biomedical Research and Study Centre, Riga, Latvia.
authors.forename: J
authors.initials: J
authors.lastname: Klovins
authors.affiliation: Department of Biochemistry and Clinical Analysis, Faculty of Pharmacy, University of Sarajevo, Sarajevo, Bosnia and Herzegovina.|International University of Sarajevo, Faculty of Engineering and Natural Sciences, Sarajevo, Bosnia and Herzegovina.
authors.forename: S
authors.initials: S
authors.lastname: Semiz
authors.affiliation: Department of Internal Medicine 4, Faculty of Medicine, Šafárik University, Košice, Slovakia.|Pasteur University Hospital, Košice, Slovakia.
authors.forename: I
authors.initials: I
authors.lastname: Tkáč
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.|Inspectorate of Healthcare, Utrecht, The Netherlands.|Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: B H
authors.initials: BH
authors.lastname: Stricker
authors.affiliation: Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee, UK.
authors.forename: Cna
authors.initials: C
authors.lastname: Palmer
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.|Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.|Department of Epidemiology and Biostatistics, EMGO+ Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: L M
authors.initials: LM
authors.lastname: 't Hart
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.|Institute for Human Genetics, University of California, San Francisco, San Francisco, California, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Giacomini
authors.affiliation: Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee, UK.
authors.forename: E R
authors.initials: ER
authors.lastname: Pearson
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D016208:Databases, Factual; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D005838:Genotype; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D050811:Octamer Transcription Factor-1 / Q000235:genetics / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D000075102:Organic Cation Transporter 2; D000071184:Pharmacogenomic Variants; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D027981:Symporters; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D026901:Membrane Transport Proteins; D008687:Metformin; D050811:Octamer Transcription Factor-1; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; D027981:Symporters; C494165:POU2F1 protein, human; C491013:SLC22A2 protein, human; C109807:SLC22A4 protein, human; C521869:SLC47A1 protein, human; C521870:SLC47A2 protein, human; C517652:hemoglobin A1c protein, human