高密度脂蛋白胆固醇对他汀类药物反应的全基因组关联研究的荟萃分析。
Meta-analysis of genome-wide association studies of HDL cholesterol response to statins.
作者信息
Postmus Iris, Warren Helen R, Trompet Stella, Arsenault Benoit J, Avery Christy L, Bis Joshua C, Chasman Daniel I, de Keyser Catherine E, Deshmukh Harshal A, Evans Daniel S, Feng QiPing, Li Xiaohui, Smit Roelof A J, Smith Albert V, Sun Fangui, Taylor Kent D, Arnold Alice M, Barnes Michael R, Barratt Bryan J, Betteridge John, Boekholdt S Matthijs, Boerwinkle Eric, Buckley Brendan M, Chen Y-D Ida, de Craen Anton J M, Cummings Steven R, Denny Joshua C, Dubé Marie Pierre, Durrington Paul N, Eiriksdottir Gudny, Ford Ian, Guo Xiuqing, Harris Tamara B, Heckbert Susan R, Hofman Albert, Hovingh G Kees, Kastelein John J P, Launer Leonore J, Liu Ching-Ti, Liu Yongmei, Lumley Thomas, McKeigue Paul M, Munroe Patricia B, Neil Andrew, Nickerson Deborah A, Nyberg Fredrik, O'Brien Eoin, O'Donnell Christopher J, Post Wendy, Poulter Neil, Vasan Ramachandran S, Rice Kenneth, Rich Stephen S, Rivadeneira Fernando, Sattar Naveed, Sever Peter, Shaw-Hawkins Sue, Shields Denis C, Slagboom P Eline, Smith Nicholas L, Smith Joshua D, Sotoodehnia Nona, Stanton Alice, Stott David J, Stricker Bruno H, Stürmer Til, Uitterlinden André G, Wei Wei-Qi, Westendorp Rudi G J, Whitsel Eric A, Wiggins Kerri L, Wilke Russell A, Ballantyne Christie M, Colhoun Helen M, Cupples L Adrienne, Franco Oscar H, Gudnason Vilmundur, Hitman Graham, Palmer Colin N A, Psaty Bruce M, Ridker Paul M, Stafford Jeanette M, Stein Charles M, Tardif Jean-Claude, Caulfield Mark J, Jukema J Wouter, Rotter Jerome I, Krauss Ronald M
机构信息
Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
Department of Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.
出版信息
J Med Genet. 2016 Dec;53(12):835-845. doi: 10.1136/jmedgenet-2016-103966. Epub 2016 Sep 1.
BACKGROUND
In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Inter-individual variation in HDL-C response to statins may be partially explained by genetic variation.
METHODS AND RESULTS
We performed a meta-analysis of genome-wide association studies (GWAS) to identify variants with an effect on statin-induced high density lipoprotein cholesterol (HDL-C) changes. The 123 most promising signals with p<1×10 from the 16 769 statin-treated participants in the first analysis stage were followed up in an independent group of 10 951 statin-treated individuals, providing a total sample size of 27 720 individuals. The only associations of genome-wide significance (p<5×10) were between minor alleles at the CETP locus and greater HDL-C response to statin treatment.
CONCLUSIONS
Based on results from this study that included a relatively large sample size, we suggest that CETP may be the only detectable locus with common genetic variants that influence HDL-C response to statins substantially in individuals of European descent. Although CETP is known to be associated with HDL-C, we provide evidence that this pharmacogenetic effect is independent of its association with baseline HDL-C levels.
背景
除了降低低密度脂蛋白胆固醇（LDL-C）外，他汀类药物治疗还可提高高密度脂蛋白胆固醇（HDL-C）水平。HDL-C对他汀类药物反应的个体间差异可能部分由基因变异解释。
方法与结果
我们进行了一项全基因组关联研究（GWAS）的荟萃分析，以确定对他汀类药物诱导的高密度脂蛋白胆固醇（HDL-C）变化有影响的变异。在第一个分析阶段，对16769名接受他汀类药物治疗的参与者中123个最有希望的信号（p<1×10），在一个由10951名接受他汀类药物治疗的独立个体组中进行随访，提供了总共27720名个体的样本量。全基因组显著性（p<5×10）的唯一关联是CETP基因座的次要等位基因与对他汀类药物治疗更大的HDL-C反应之间。
结论
基于这项包括相对大样本量的研究结果，我们认为CETP可能是在欧洲血统个体中唯一可检测到的具有常见基因变异的基因座，其对HDL-C对他汀类药物的反应有实质性影响。尽管已知CETP与HDL-C相关，但我们提供的证据表明这种药物遗传学效应独立于其与基线HDL-C水平的关联。
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