TY - JOUR
T1 - Variants in Pharmacokinetic Transporters and Glycemic Response to Metformin
T2 - A Metgen Meta-Analysis
AU - Dujic, T.
AU - Zhou, K.
AU - Yee, S. W.
AU - van Leeuwen, N.
AU - de Keyser, C. E.
AU - Javorský, M.
AU - Goswami, S.
AU - Zaharenko, L.
AU - Hougaard Christensen, M. M.
AU - Out, M.
AU - Tavendale, R.
AU - Kubo, M.
AU - Hedderson, M. M.
AU - van der Heijden, A. A.
AU - Klimčáková, L.
AU - Pirags, V.
AU - Kooy, A.
AU - Brøsen, K.
AU - Klovins, J.
AU - Semiz, S.
AU - Tkáč, I.
AU - Stricker, B. H.
AU - Palmer, C. N.A.
AU - 't Hart, L. M.
AU - Giacomini, K. M.
AU - Pearson, E. R.
N1 - Funding Information:
DCS: The DCS study is supported by the Diabetes Care System West-Friesland, the Netherlands. This part of the study was funded by the Netherlands Organisation for Health Research and Development (Priority Medicines Elderly Programme 113102006) and by the Innovative Medicines Initiative Joint Undertaking under grant agreement number 115317 (DIRECT), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies' in kind contribution (http://www.direct-diabetes.org/). GoDARTS: We are grateful to all the participants who took part in this study, to the general practitioners, to the Scottish School of Primary Care for their help in recruiting the participants, and to the whole team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. The Wellcome Trust United Kingdom Type 2 Diabetes Case Control Collection (GoDARTS) cohort collection was funded by The Wellcome Trust and informatics support was provided by the Chief Scientist Office, Scotland. E.R.P. holds a Wellcome Trust New Investigator Award (102820/Z/13/Z). Košice: The study was supported by research grants VEGA 1/0389/14 and VEGA 1/0027/16 from the Ministry of Education, Science, Research and Sport, Slovak Republic. PMT1 & PMT2: K.M.G., S.W.Y., and S.G. would like to acknowledge support from NIH grants (GM117163, T32 GM007175). The genotyping of the PMT1-EU was supported by the National Institutes of Health (U19 GM061390) and the RIKEN Institute. The genotyping of the GERA cohort (called PMT2-EU in this study) was supported by grant RC2 AG036607 from the National Institutes of Health; development of the RPGEH and GERA cohort was supported by grants from the Robert Wood Johnson Foundation, the Ellison Medical Foundation, the Wayne and Gladys Valley Foundation, and Kaiser Permanente. We would like to acknowledge BioVU (Vanderbilt DNA databank), The Marshfield Clinic Personalized Medicine Research Project (PMRP), and Kaiser Permanente South East Georgia for collecting the clinical information for PMT1-EU. Sarajevo: The study was supported by grants received from the Council of Ministers/Ministry of Civil Affairs of Bosnia and Herzegovina and the Federal Ministry for Education and Science of Bosnia and Herzegovina awarded to S.S., and by a European Foundation for the Study of Diabetes Albert Renold Travel Fellowship to T.D. SDDS: K.B. acknowledges support from AJ Andersen and Wife's Foundation (J. No. 01737-0005), the AP Moeller Foundation for the Advancement of Medical Science (J. No. 09034), and the Region of Southern Denmark (J. No. 09/12913).
Publisher Copyright:
© 2017 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics
PY - 2017/6/1
Y1 - 2017/6/1
N2 - 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.
AB - 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.
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U2 - 10.1002/cpt.567
DO - 10.1002/cpt.567
M3 - Article
C2 - 27859023
AN - SCOPUS:85012060225
SN - 0009-9236
VL - 101
SP - 763
EP - 772
JO - Clinical Pharmacology and Therapeutics
JF - Clinical Pharmacology and Therapeutics
IS - 6
ER -