A gene variant near ATM affects the response to metformin and metformin plasma levels: a post hoc analysis of an RCT

Mattijs Out; Matthijs L. Becker; Ron H. van Schaik; Philippe Lehert; Coen D. Stehouwer; Adriaan Kooy

doi:10.2217/pgs-2018-0010

A gene variant near ATM affects the response to metformin and metformin plasma levels: a post hoc analysis of an RCT

Mattijs Out, Matthijs L. Becker, Ron H. van Schaik, Philippe Lehert, Coen D. Stehouwer, Adriaan Kooy^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Aim: To determine the influence of polymorphisms on the effects of metformin on HbA1c, daily dose of insulin and metformin plasma concentration. Methods: In a post hoc analysis of a 4.3 year placebo-controlled randomized trial with 390 patients with Type 2 diabetes already on insulin, we analyzed the influence of polymorphisms in genes coding for ATM and the transporters OCT1 and MATE1. Outcome measures were a combined HbA1c + daily dose of insulin Z score and metformin plasma concentrations. Results: rs11212617 (ATM) was associated with an improved Z score and a lower metformin plasma concentration. In addition, the major allele of rs2289669 (MATE1) was also associated with an improved Z score. Conclusion: The ATM SNR rs11212617 significantly affected the effect of metformin and metformin plasma concentration. Further research is needed to determine the clinical importance of these findings, in particular the effects on metformin plasma concentration.

Original language	English
Pages (from-to)	715-726
Number of pages	12
Journal	Pharmacogenomics
Volume	19
Issue number	8
DOIs	https://doi.org/10.2217/pgs-2018-0010
Publication status	Published - 1 Jun 2018

Keywords

ATM protein
dose-response relationship
drug
human
metformin
CATION TRANSPORTER 1
TYPE-2 DIABETES-MELLITUS
TOXIN EXTRUSION 1
ATAXIA-TELANGIECTASIA
INSULIN-RESISTANCE
GLYCEMIC RESPONSE
SLC47A1 GENE
PHARMACOKINETICS
OCT1
POLYMORPHISMS

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10.2217/pgs-2018-0010

Cite this

@article{2020663184b249cbb66d5eb082a9ea50,

title = "A gene variant near ATM affects the response to metformin and metformin plasma levels: a post hoc analysis of an RCT",

abstract = "Aim: To determine the influence of polymorphisms on the effects of metformin on HbA1c, daily dose of insulin and metformin plasma concentration. Methods: In a post hoc analysis of a 4.3 year placebo-controlled randomized trial with 390 patients with Type 2 diabetes already on insulin, we analyzed the influence of polymorphisms in genes coding for ATM and the transporters OCT1 and MATE1. Outcome measures were a combined HbA1c + daily dose of insulin Z score and metformin plasma concentrations. Results: rs11212617 (ATM) was associated with an improved Z score and a lower metformin plasma concentration. In addition, the major allele of rs2289669 (MATE1) was also associated with an improved Z score. Conclusion: The ATM SNR rs11212617 significantly affected the effect of metformin and metformin plasma concentration. Further research is needed to determine the clinical importance of these findings, in particular the effects on metformin plasma concentration.",

keywords = "ATM protein, dose-response relationship, drug, human, metformin, CATION TRANSPORTER 1, TYPE-2 DIABETES-MELLITUS, TOXIN EXTRUSION 1, ATAXIA-TELANGIECTASIA, INSULIN-RESISTANCE, GLYCEMIC RESPONSE, SLC47A1 GENE, PHARMACOKINETICS, OCT1, POLYMORPHISMS",

author = "Mattijs Out and Becker, {Matthijs L.} and {van Schaik}, {Ron H.} and Philippe Lehert and Stehouwer, {Coen D.} and Adriaan Kooy",

year = "2018",

month = jun,

day = "1",

doi = "10.2217/pgs-2018-0010",

language = "English",

volume = "19",

pages = "715--726",

journal = "Pharmacogenomics",

issn = "1462-2416",

publisher = "Future Medicine Ltd.",

number = "8",

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TY - JOUR

T1 - A gene variant near ATM affects the response to metformin and metformin plasma levels: a post hoc analysis of an RCT

AU - Out, Mattijs

AU - Becker, Matthijs L.

AU - van Schaik, Ron H.

AU - Lehert, Philippe

AU - Stehouwer, Coen D.

AU - Kooy, Adriaan

PY - 2018/6/1

Y1 - 2018/6/1

N2 - Aim: To determine the influence of polymorphisms on the effects of metformin on HbA1c, daily dose of insulin and metformin plasma concentration. Methods: In a post hoc analysis of a 4.3 year placebo-controlled randomized trial with 390 patients with Type 2 diabetes already on insulin, we analyzed the influence of polymorphisms in genes coding for ATM and the transporters OCT1 and MATE1. Outcome measures were a combined HbA1c + daily dose of insulin Z score and metformin plasma concentrations. Results: rs11212617 (ATM) was associated with an improved Z score and a lower metformin plasma concentration. In addition, the major allele of rs2289669 (MATE1) was also associated with an improved Z score. Conclusion: The ATM SNR rs11212617 significantly affected the effect of metformin and metformin plasma concentration. Further research is needed to determine the clinical importance of these findings, in particular the effects on metformin plasma concentration.

AB - Aim: To determine the influence of polymorphisms on the effects of metformin on HbA1c, daily dose of insulin and metformin plasma concentration. Methods: In a post hoc analysis of a 4.3 year placebo-controlled randomized trial with 390 patients with Type 2 diabetes already on insulin, we analyzed the influence of polymorphisms in genes coding for ATM and the transporters OCT1 and MATE1. Outcome measures were a combined HbA1c + daily dose of insulin Z score and metformin plasma concentrations. Results: rs11212617 (ATM) was associated with an improved Z score and a lower metformin plasma concentration. In addition, the major allele of rs2289669 (MATE1) was also associated with an improved Z score. Conclusion: The ATM SNR rs11212617 significantly affected the effect of metformin and metformin plasma concentration. Further research is needed to determine the clinical importance of these findings, in particular the effects on metformin plasma concentration.

KW - ATM protein

KW - dose-response relationship

KW - drug

KW - human

KW - metformin

KW - CATION TRANSPORTER 1

KW - TYPE-2 DIABETES-MELLITUS

KW - TOXIN EXTRUSION 1

KW - ATAXIA-TELANGIECTASIA

KW - INSULIN-RESISTANCE

KW - GLYCEMIC RESPONSE

KW - SLC47A1 GENE

KW - PHARMACOKINETICS

KW - OCT1

KW - POLYMORPHISMS

U2 - 10.2217/pgs-2018-0010

DO - 10.2217/pgs-2018-0010

M3 - Article

C2 - 29790415

SN - 1462-2416

VL - 19

SP - 715

EP - 726

JO - Pharmacogenomics

JF - Pharmacogenomics

IS - 8

ER -