Genomewide Association Study of Platelet Reactivity and Cardiovascular Response in Patients Treated With Clopidogrel: A Study by the International Clopidogrel Pharmacogenomics Consortium.
Genomewide Association Study of Platelet Reactivity and Cardiovascular Response in Patients Treated With Clopidogrel: A Study by the International Clopidogrel Pharmacogenomics Consortium.
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DOI：
10.1002/cpt.1911
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发表时间：
2020-11
影响因子：
6.7
通讯作者：
ICPC Investigators
中科院分区：
文献类型：
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作者：
Verma SS;Bergmeijer TO;Gong L;Reny JL;Lewis JP;Mitchell BD;Alexopoulos D;Aradi D;Altman RB;Bliden K;Bradford Y;Campo G;Chang K;Cleator JH;Déry JP;Dridi NP;Fernandez-Cadenas I;Fontana P;Gawaz M;Geisler T;Gensini GF;Giusti B;Gurbel PA;Hochholzer W;Holmvang L;Kim EY;Kim HS;Marcucci R;Montaner J;Backman JD;Pakyz RE;Roden DM;Schaeffeler E;Schwab M;Shin JG;Siller-Matula JM;Ten Berg JM;Trenk D;Valgimigli M;Wallace J;Wen MS;Kubo M;Lee MTM;Whaley R;Winter S;Klein TE;Shuldiner AR;Ritchie MD;ICPC Investigators
氯吡格雷的抗血小板反应差异很大，不良反应与不良临床结局相关。CYP2C19功能丧失等位基因在这种应答中发挥重要作用，但仅占氯吡格雷应答变异性的一小部分。国际氯吡格雷药物基因组学联盟（ICPC）的一个目的是确定氯吡格雷药效学和临床反应的其他遗传决定因素。使用来自2，750名欧洲血统个体的DNA进行全基因组关联研究（GWAS），使用腺苷二磷酸诱导的血小板反应性和主要心脑血管事件作为结局参数。血小板反应性的GWAS显示CYP2C19*2的强信号（P值= 1.67e−33）。校正CYP2C19*2后，没有其他单核苷酸多态性达到全基因组显著性。GWAS用于心血管死亡、心肌梗死或卒中的联合临床终点（事件发生率5.0%），或心血管死亡或心肌梗死的联合终点（4.7%的事件发生率）显示无显著结果，尽管在冠状动脉疾病、经皮冠状动脉介入治疗和急性冠状动脉综合征亚组中，SCOS5P1、CDC 42 BPA、和CTRAC 1显示出全基因组显著性（最低P值分别为1.07e−09、4.53e−08和2.60e−10）。CYP2C19*2是氯吡格雷血小板反应性的最强遗传决定因素。我们在临床结果亚组中发现了三种新的相关性，提示了这些结果中的每一种。
Antiplatelet response to clopidogrel shows wide variation, and poor response is correlated with adverse clinical outcomes. CYP2C19 loss‐of‐function alleles play an important role in this response, but account for only a small proportion of variability in response to clopidogrel. An aim of the International Clopidogrel Pharmacogenomics Consortium (ICPC) is to identify other genetic determinants of clopidogrel pharmacodynamics and clinical response. A genomewide association study (GWAS) was performed using DNA from 2,750 European ancestry individuals, using adenosine diphosphate‐induced platelet reactivity and major cardiovascular and cerebrovascular events as outcome parameters. GWAS for platelet reactivity revealed a strong signal for CYP2C19*2 (P value = 1.67e−33). After correction for CYP2C19*2 no other single‐nucleotide polymorphism reached genomewide significance. GWAS for a combined clinical end point of cardiovascular death, myocardial infarction, or stroke (5.0% event rate), or a combined end point of cardiovascular death or myocardial infarction (4.7% event rate) showed no significant results, although in coronary artery disease, percutaneous coronary intervention, and acute coronary syndrome subgroups, mutations in SCOS5P1, CDC42BPA, and CTRAC1 showed genomewide significance (lowest P values: 1.07e−09, 4.53e−08, and 2.60e−10, respectively). CYP2C19*2 is the strongest genetic determinant of on‐clopidogrel platelet reactivity. We identified three novel associations in clinical outcome subgroups, suggestive for each of these outcomes.
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DOI：
10.1161/circgen.117.002069
发表时间：
2018-04
期刊：
Circulation. Genomic and precision medicine
影响因子：
--
作者：
Lee CR;Sriramoju VB;Cervantes A;Howell LA;Varunok N;Madan S;Hamrick K;Polasek MJ;Lee JA;Clarke M;Cicci JD;Weck KE;Stouffer GA
通讯作者：
Stouffer GA
影响因子：
9.2
作者：
Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
通讯作者：
Lee JJ
影响因子：
2.1
作者：
Geisler, Tobias;Schaeffeler, Elke;Schwab, Matthias
通讯作者：
Schwab, Matthias
影响因子：
11.3
作者：
Angiolillo, Dominick J.;Capodanno, Davide;Price, Matthew J.
通讯作者：
Price, Matthew J.
影响因子：
3.1
作者：
Ben Romdhan, Sawssan;Sakka, Salma;Mhiri, Chokri
通讯作者：
Mhiri, Chokri