A common variant at 9p21 is associated with sudden and arrhythmic cardiac death.
A common variant at 9p21 is associated with sudden and arrhythmic cardiac death.
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DOI：
10.1161/circulationaha.109.879049
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发表时间：
2009-11-24
期刊：
影响因子：
37.8
通讯作者：
Albert CM
中科院分区：
文献类型：
--
作者：
Newton-Cheh C;Cook NR;VanDenburgh M;Rimm EB;Ridker PM;Albert CM
虽然心脏性猝死（SCD）的遗传基础是由家族史对SCD风险的影响提出的，但遗传决定因素一直难以确定。我们假设与心肌梗死相关的染色体9 p21的常见变异会影响SCD风险。在6项前瞻性队列研究中招募的高加索血统个体中进行前瞻性巢式病例对照分析。研究对象随访SCD的发展，并确定了492例猝死和/或猝死的rs 10757274基因型，以及1460例年龄、性别、队列、心血管疾病（CVD）史和随访时间相匹配的对照。假设使用加性模型来检验关联性，采用固定效应荟萃分析的条件逻辑回归。当在荟萃分析中合并个体研究结果时，rs 10757274处G等位基因拷贝数每增加一次，SCD的年龄校正比值比就显著升高，等于1.21（95%CI，1.04-1.40; P=0.01）。心血管和生活方式危险因素的控制加强了这些关系（OR=1.29/G等位基因拷贝，95%CI：1.09-1.53，p=0.003）。在仅限于明确SCD或进一步控制CVD发展的模型的敏感性分析中，或当检测高度相关的变体rs 2383207时，这些结果未发生实质性改变。先前与冠心病事件风险增加相关的SNP的主要等位基因与欧洲血统个体的SCD风险增加相关。研究这种关联的机制可能会提高我们对致命性CVD的理解。
While a heritable basis for sudden cardiac death (SCD) is suggested by the impact of family history on SCD risk, genetic determinants have been difficult to identify. We hypothesized that a common variant at chromosome 9p21 related to myocardial infarction would influence SCD risk. Prospective, nested case-control analysis among individuals of Caucasian ancestry enrolled in six prospective cohort studies. Study subjects were followed for development of SCD, and genotypes for rs10757274 were determined for 492 sudden and/or arrhythmic deaths and 1460 controls matched on age, sex, cohort, history of cardiovascular disease (CVD) and follow-up time. Conditional logistic regression with fixed effects meta-analysis assuming an additive model was used to test for associations. When individual study results were combined in meta-analysis, each increasing copy of the G-allele at rs10757274 conferred a significantly elevated age-adjusted odds ratio for SCD equal to 1.21 (95% CI, 1.04–1.40; P=0.01). Control for cardiovascular and lifestyle risk factors strengthened these relationships (OR=1.29/G-allele copy, 95%CI: 1.09–1.53, p=0.003). These results were not materially altered in sensitivity analyses limited to definite SCDs or models that further controlled for the development of CVD or when a highly correlated variant rs2383207 was tested. The major allele of a SNP previously associated with increased risk of coronary artery disease events is associated with increased risk of SCD in individuals of European ancestry. Study of the mechanism underlying this association may improve our understanding of lethal CVD.