Heritability of variation in glycaemic response to metformin: a genome-wide complex trait analysis.
Heritability of variation in glycaemic response to metformin: a genome-wide complex trait analysis.
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DOI：
10.1016/s2213-8587(14)70050-6
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发表时间：
2014-06
影响因子：
44.5
通讯作者：
Pearson, Ewan R.
中科院分区：
文献类型：
--
作者：
Zhou, Kaixin;Donnelly, Louise;Yang, Jian;Li, Miaoxin;Deshmukh, Harshal;Van Zuydam, Natalie;Ahlqvist, Emma;Spencer, Chris C.;Groop, Leif;Morris, Andrew D.;Colhoun, Helen M.;Sham, Pak C.;McCarthy, Mark I.;Palmer, Colin N. A.;Pearson, Ewan R.
二甲双胍是用于治疗2型糖尿病的一线口服药物，但对该药物的血药反应差异很大。了解遗传因素对二甲双胍反应的影响可能会增加二甲双胍治疗个性化的可能性。我们的目的是使用全基因组复杂性状分析（GCTA）方法建立二甲双胍治疗后贫血反应的遗传率。在这项GCTA研究中，我们从苏格兰泰赛德糖尿病遗传学审核和研究（GoDARTS）研究中的患者中获得了二甲双胍治疗前和治疗期间的HbA 1c浓度数据，该研究包括一组2型糖尿病患者，并与综合临床数据库和全基因组关联研究数据相关联。我们应用GCTA方法估计了二甲双胍治疗后的4种贫血应答定义的遗传性：HbA 1c绝对降低; HbA 1c成比例降低;调整后的HbA 1c降低;以及是否达到低于7%（53 mmol/mol）的治疗中HbA 1c目标，并对基线HbA 1c和已知的临床协变量进行了调整。染色体遗传力估计用于获得有关遗传结构的进一步信息。最终数据集中纳入了5386例患者，其中2085例患者有足够的临床数据来确定二甲双胍的不良反应。二甲双胍的血药应答的遗传率因应答表型而异，HbA 1c绝对降低的遗传率为34%（95% CI 1-68; p= 0.022），根据治疗前HbA 1c进行校正。染色体遗传力估计表明，遗传贡献可能来自分散在基因组中的个体变异，每个变异都有小到中等的影响，而不是来自几个基因座，每个基因座都有很大的影响。对二甲双胍的血糖反应是可遗传的，因此对二甲双胍的血糖反应部分是个体生物学变异的内在原因。进一步的遗传分析可能使我们能够更好地预测分层药物，并揭示二甲双胍作用的新机制。Wellcome Trust.
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. In this GCTA study, we obtained data about HbA1c concentrations 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. 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. 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. Wellcome Trust.