Heritability of variation in glycaemic response to metformin

a genome-wide complex trait analysis

Kaixin Zhou (Lead / Corresponding author), Louise Donnelly, Jian Yang, Miaoxin Li, Harshal Deshmukh, Natalie Van Zuydam, Emma Ahlqvist, Chris C. Spencer, Lief Groop, Andrew D. Morris, Helen M. Colhoun, Pak C. Sham, Mark I. McCarthy, Colin N.A. Palmer, Ewan R. Pearson

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    Abstract

    Background: Metformin is a first-line oral agent used in the treatment of type 2 diabetes, but glycaemic response to this drug is highly variable. Understanding the genetic contribution to metformin response might increase the possibility of personalising metformin treatment. We aimed to establish the heritability of glycaemic response to metformin using the genome-wide complex trait analysis (GCTA) method. Methods: In this GCTA study, we obtained data about HbA 1cconcentrations before and during metformin treatment from patients in the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) study, which includes a cohort of patients with type 2 diabetes and is linked to comprehensive clinical databases and genome-wide association study data. We applied the GCTA method to estimate heritability for four definitions of glycaemic response to metformin: absolute reduction in HbA1c; proportional reduction in HbA1c; adjusted reduction in HbA1c; and whether or not the target on-treatment HbA1c of less than 7% (53 mmol/mol) was achieved, with adjustment for baseline HbA1c and known clinical covariates. Chromosome-wise heritability estimation was used to obtain further information about the genetic architecture. Findings: 5386 individuals were included in the final dataset, of whom 2085 had enough clinical data to define glycaemic response to metformin. The heritability of glycaemic response to metformin varied by response phenotype, with a heritability of 34% (95% CI 1-68; p=0·022) for the absolute reduction in HbA1c, adjusted for pretreatment HbA1c. Chromosome-wise heritability estimates suggest that the genetic contribution is probably from individual variants scattered across the genome, which each have a small to moderate effect, rather than from a few loci that each have a large effect. Interpretation: Glycaemic response to metformin is heritable, thus glycaemic response to metformin is, in part, intrinsic to individual biological variation. Further genetic analysis might enable us to make better predictions for stratified medicine and to unravel new mechanisms of metformin action.

    Original languageEnglish
    Pages (from-to)481-487
    Number of pages7
    JournalThe Lancet: Diabetes and Endocrinology
    Volume2
    Issue number6
    DOIs
    Publication statusPublished - Jun 2014

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    Metformin
    Genome
    Type 2 Diabetes Mellitus
    Chromosomes
    Genome-Wide Association Study
    Scotland
    Therapeutics
    Medicine
    Databases
    Phenotype

    Cite this

    Zhou, Kaixin ; Donnelly, Louise ; Yang, Jian ; Li, Miaoxin ; Deshmukh, Harshal ; Van Zuydam, Natalie ; Ahlqvist, Emma ; Spencer, Chris C. ; Groop, Lief ; Morris, Andrew D. ; Colhoun, Helen M. ; Sham, Pak C. ; McCarthy, Mark I. ; Palmer, Colin N.A. ; Pearson, Ewan R. / Heritability of variation in glycaemic response to metformin : a genome-wide complex trait analysis. In: The Lancet: Diabetes and Endocrinology. 2014 ; Vol. 2, No. 6. pp. 481-487.
    @article{5c5b7d9c16e74986b71d6b63c8fa0359,
    title = "Heritability of variation in glycaemic response to metformin: a genome-wide complex trait analysis",
    abstract = "Background: Metformin is a first-line oral agent used in the treatment of type 2 diabetes, but glycaemic response to this drug is highly variable. Understanding the genetic contribution to metformin response might increase the possibility of personalising metformin treatment. We aimed to establish the heritability of glycaemic response to metformin using the genome-wide complex trait analysis (GCTA) method. Methods: In this GCTA study, we obtained data about HbA 1cconcentrations before and during metformin treatment from patients in the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) study, which includes a cohort of patients with type 2 diabetes and is linked to comprehensive clinical databases and genome-wide association study data. We applied the GCTA method to estimate heritability for four definitions of glycaemic response to metformin: absolute reduction in HbA1c; proportional reduction in HbA1c; adjusted reduction in HbA1c; and whether or not the target on-treatment HbA1c of less than 7{\%} (53 mmol/mol) was achieved, with adjustment for baseline HbA1c and known clinical covariates. Chromosome-wise heritability estimation was used to obtain further information about the genetic architecture. Findings: 5386 individuals were included in the final dataset, of whom 2085 had enough clinical data to define glycaemic response to metformin. The heritability of glycaemic response to metformin varied by response phenotype, with a heritability of 34{\%} (95{\%} CI 1-68; p=0·022) for the absolute reduction in HbA1c, adjusted for pretreatment HbA1c. Chromosome-wise heritability estimates suggest that the genetic contribution is probably from individual variants scattered across the genome, which each have a small to moderate effect, rather than from a few loci that each have a large effect. Interpretation: Glycaemic response to metformin is heritable, thus glycaemic response to metformin is, in part, intrinsic to individual biological variation. Further genetic analysis might enable us to make better predictions for stratified medicine and to unravel new mechanisms of metformin action.",
    author = "Kaixin Zhou and Louise Donnelly and Jian Yang and Miaoxin Li and Harshal Deshmukh and {Van Zuydam}, Natalie and Emma Ahlqvist and Spencer, {Chris C.} and Lief Groop and Morris, {Andrew D.} and Colhoun, {Helen M.} and Sham, {Pak C.} and McCarthy, {Mark I.} and Palmer, {Colin N.A.} and Pearson, {Ewan R.}",
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    year = "2014",
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    doi = "10.1016/S2213-8587(14)70050-6",
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    Zhou, K, Donnelly, L, Yang, J, Li, M, Deshmukh, H, Van Zuydam, N, Ahlqvist, E, Spencer, CC, Groop, L, Morris, AD, Colhoun, HM, Sham, PC, McCarthy, MI, Palmer, CNA & Pearson, ER 2014, 'Heritability of variation in glycaemic response to metformin: a genome-wide complex trait analysis', The Lancet: Diabetes and Endocrinology, vol. 2, no. 6, pp. 481-487. https://doi.org/10.1016/S2213-8587(14)70050-6

    Heritability of variation in glycaemic response to metformin : a genome-wide complex trait analysis. / Zhou, Kaixin (Lead / Corresponding author); Donnelly, Louise; Yang, Jian; Li, Miaoxin; Deshmukh, Harshal; Van Zuydam, Natalie; Ahlqvist, Emma; Spencer, Chris C.; Groop, Lief; Morris, Andrew D.; Colhoun, Helen M.; Sham, Pak C.; McCarthy, Mark I.; Palmer, Colin N.A.; Pearson, Ewan R.

    In: The Lancet: Diabetes and Endocrinology, Vol. 2, No. 6, 06.2014, p. 481-487.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Heritability of variation in glycaemic response to metformin

    T2 - a genome-wide complex trait analysis

    AU - Zhou, Kaixin

    AU - Donnelly, Louise

    AU - Yang, Jian

    AU - Li, Miaoxin

    AU - Deshmukh, Harshal

    AU - Van Zuydam, Natalie

    AU - Ahlqvist, Emma

    AU - Spencer, Chris C.

    AU - Groop, Lief

    AU - Morris, Andrew D.

    AU - Colhoun, Helen M.

    AU - Sham, Pak C.

    AU - McCarthy, Mark I.

    AU - Palmer, Colin N.A.

    AU - Pearson, Ewan R.

    N1 - Copyright © 2014 Elsevier Ltd. All rights reserved.

    PY - 2014/6

    Y1 - 2014/6

    N2 - Background: Metformin is a first-line oral agent used in the treatment of type 2 diabetes, but glycaemic response to this drug is highly variable. Understanding the genetic contribution to metformin response might increase the possibility of personalising metformin treatment. We aimed to establish the heritability of glycaemic response to metformin using the genome-wide complex trait analysis (GCTA) method. Methods: In this GCTA study, we obtained data about HbA 1cconcentrations before and during metformin treatment from patients in the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) study, which includes a cohort of patients with type 2 diabetes and is linked to comprehensive clinical databases and genome-wide association study data. We applied the GCTA method to estimate heritability for four definitions of glycaemic response to metformin: absolute reduction in HbA1c; proportional reduction in HbA1c; adjusted reduction in HbA1c; and whether or not the target on-treatment HbA1c of less than 7% (53 mmol/mol) was achieved, with adjustment for baseline HbA1c and known clinical covariates. Chromosome-wise heritability estimation was used to obtain further information about the genetic architecture. Findings: 5386 individuals were included in the final dataset, of whom 2085 had enough clinical data to define glycaemic response to metformin. The heritability of glycaemic response to metformin varied by response phenotype, with a heritability of 34% (95% CI 1-68; p=0·022) for the absolute reduction in HbA1c, adjusted for pretreatment HbA1c. Chromosome-wise heritability estimates suggest that the genetic contribution is probably from individual variants scattered across the genome, which each have a small to moderate effect, rather than from a few loci that each have a large effect. Interpretation: Glycaemic response to metformin is heritable, thus glycaemic response to metformin is, in part, intrinsic to individual biological variation. Further genetic analysis might enable us to make better predictions for stratified medicine and to unravel new mechanisms of metformin action.

    AB - Background: Metformin is a first-line oral agent used in the treatment of type 2 diabetes, but glycaemic response to this drug is highly variable. Understanding the genetic contribution to metformin response might increase the possibility of personalising metformin treatment. We aimed to establish the heritability of glycaemic response to metformin using the genome-wide complex trait analysis (GCTA) method. Methods: In this GCTA study, we obtained data about HbA 1cconcentrations before and during metformin treatment from patients in the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) study, which includes a cohort of patients with type 2 diabetes and is linked to comprehensive clinical databases and genome-wide association study data. We applied the GCTA method to estimate heritability for four definitions of glycaemic response to metformin: absolute reduction in HbA1c; proportional reduction in HbA1c; adjusted reduction in HbA1c; and whether or not the target on-treatment HbA1c of less than 7% (53 mmol/mol) was achieved, with adjustment for baseline HbA1c and known clinical covariates. Chromosome-wise heritability estimation was used to obtain further information about the genetic architecture. Findings: 5386 individuals were included in the final dataset, of whom 2085 had enough clinical data to define glycaemic response to metformin. The heritability of glycaemic response to metformin varied by response phenotype, with a heritability of 34% (95% CI 1-68; p=0·022) for the absolute reduction in HbA1c, adjusted for pretreatment HbA1c. Chromosome-wise heritability estimates suggest that the genetic contribution is probably from individual variants scattered across the genome, which each have a small to moderate effect, rather than from a few loci that each have a large effect. Interpretation: Glycaemic response to metformin is heritable, thus glycaemic response to metformin is, in part, intrinsic to individual biological variation. Further genetic analysis might enable us to make better predictions for stratified medicine and to unravel new mechanisms of metformin action.

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    U2 - 10.1016/S2213-8587(14)70050-6

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    JO - The Lancet: Diabetes and Endocrinology

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    SN - 2213-8587

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