血管紧张素转换酶抑制剂不耐受性的全基因组关联研究的荟萃分析
Meta-analysis of genome-wide association studies on the intolerance of angiotensin-converting enzyme inhibitors.
作者信息
Mahmoudpour Seyed H, Veluchamy Abirami, Siddiqui Moneeza K, Asselbergs Folkert W, Souverein Patrick C, de Keyser Catherine E, Hofman Albert, Lang Chim C, Doney Alexander S F, Stricker Bruno H, de Boer Anthonius, Maitland-van der Zee Anke H, Palmer Colin N A
机构信息
aDepartment of Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University bDepartment of Cardiology, Division of Heart and Lungs, University Medical Center cDurrer Centre for Cardiovascular Research, Netherlands Heart Institute, Utrecht dDepartment of Epidemiology, Erasmus Medical Center, Rotterdam eDepartment of Respiratory Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands fCentre for Pharmacogenetics and Pharmacogenomics, Medical Research Institute, Ninewells Hospital and School of Medicine, University of Dundee, Dundee gInstitute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, UK hDepartment of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
出版信息
Pharmacogenet Genomics. 2017 Mar;27(3):112-119. doi: 10.1097/FPC.0000000000000264.
OBJECTIVES
To identify single nucleotide polymorphisms (SNPs) associated with switching from an angiotensin-converting enzyme (ACE)-inhibitor to an angiotensin receptor blocker.
METHODS
Two cohorts of patients starting ACE-inhibitors were identified within the Rotterdam Study in the Netherlands and the Genetics of Diabetes Audit and Research in Tayside Scotland study in Scotland. Cases were intolerant patients who switched from an ACE-inhibitor to an angiotensin receptor blocker and controls were individuals who used ACE-inhibitors continuously for at least 2 years and did not switch. Genome-wide association study (GWAS) using an additive model was run in these sets and the results were meta-analysed using Genome-Wide Association Meta Analysis software.
RESULTS
A total of 972 cases out of 5161 ACE-inhibitor starters were identified. Eight SNPs within four genes reached the genome-wide association study significance level (P<5×10) in the meta-analysis [RNA binding protein, Fox-1 homolog (Caenorhabditis elegans), γ-aminobutyric acid receptor subunit γ-2, sarcoma (Src) homology 2 (SH2) B adaptor protein 1 and membrane bound O-acyltransferase domain containing 1]. The strongest associated SNP was located in an intron of RNA binding protein, Fox-1 homolog (Caenorhabditis elegans), which contains an RNA binding protein [rs2061538: minor allele frequency=0.16, odds ratio=1.52 (95% confidence interval: 1.32-1.76), P=6.2×10].
CONCLUSION
These results indicate that genetic variation in the above-mentioned genes may increase the risk of ACE-inhibitor-induced adverse reactions.
目的
确定与从血管紧张素转换酶（ACE）抑制剂转换为血管紧张素受体阻滞剂相关的单核苷酸多态性（SNP）。
方法
在荷兰的鹿特丹研究以及苏格兰泰赛德地区的糖尿病遗传审计与研究中，识别出两组开始使用ACE抑制剂的患者。病例为从ACE抑制剂转换为血管紧张素受体阻滞剂的不耐受患者，对照组为连续使用ACE抑制剂至少2年且未转换的个体。在这些样本中采用加性模型进行全基因组关联研究（GWAS），并使用全基因组关联荟萃分析软件对结果进行荟萃分析。
结果
在5161名开始使用ACE抑制剂的患者中，共识别出972例病例。在荟萃分析中，四个基因内的八个SNP达到了全基因组关联研究的显著性水平（P<5×10）[RNA结合蛋白，Fox-1同源物（秀丽隐杆线虫），γ-氨基丁酸受体亚基γ-2，肉瘤（Src）同源2（SH2）B衔接蛋白1和含膜结合O-酰基转移酶结构域1]。最强相关的SNP位于RNA结合蛋白Fox-1同源物（秀丽隐杆线虫）的一个内含子中，该内含子包含一种RNA结合蛋白[rs2061538：次要等位基因频率=0.16，优势比=1.52（95%置信区间：1.32 - 1.76），P=6.2×10]。
结论
这些结果表明，上述基因的遗传变异可能会增加ACE抑制剂引起不良反应的风险。
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