Genetic variation in NOS1AP is associated with sudden cardiac death: evidence from the Rotterdam Study
Genetic variation in NOS1AP is associated with sudden cardiac death: evidence from the Rotterdam Study
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DOI：
10.1093/hmg/ddp356
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发表时间：
2009-11-01
影响因子：
3.5
通讯作者：
Stricker, Bruno H. C.
中科院分区：
文献类型：
--
作者：
Eijgelsheim, Mark;Newton-Cheh, Christopher;Stricker, Bruno H. C.
一氧化氮合酶激活蛋白(NOS1AP)基因的常见变异与QT间期密切相关，QT间期是心源性猝死(SCD)的危险因素。最近的一份报告描述了与SCD相关的NOS1AP在欧洲血统的美国人群中的常见变异。本研究的目的是通过在鹿特丹前瞻性人群研究中调查NOS1AP变异与SCD之间的关联来获得更多证据。研究人群包括5974名欧洲血统受试者，年龄在55岁及以上，在Illumina阵列上进行基因分型。SCD是根据欧洲心脏病学会的指南定义的。在COX比例风险模型中，吸烟、体重指数、糖尿病、高血压、心力衰竭和心肌梗死作为协变量。结果与报道的证据结合使用逆方差加权荟萃分析。208例(目击)SCD发生在平均10.4年的随访期内。仅在鹿特丹的研究中，没有观察到显著的关联。将结果与现有数据合并后，我们观察到rs16847549的现有证据得到了加强(美国数据HR=1.31，P=0.0024；鹿特丹研究HR=1.18，P=0.16；联合HR=1.26，P=0.0011)。当鹿特丹研究中的病例定义被限制为目击的SCD时，rs16847549与SCD的关联变得更强(联合P=0.00019)，此外，rs12567209与SCD的关联也有显著意义(美国数据HR=0.57，P=0.0035；鹿特丹研究HR=0.69，P=0.23；联合HR=0.6，P=0.0018)。总之，这项研究为NOS1AP内的遗传变异与SCD之间的关联提供了额外的证据。这种作用的机制还有待阐明。
Common variation within the nitric oxide-1 synthase activator protein (NOS1AP) locus is strongly related to QT interval, a sudden cardiac death (SCD) risk factor. A recent report describes common variation in NOS1AP associated with SCD in a US population of European ancestry. The objective of the current study was to obtain additional evidence by investigating the association between NOS1AP variants and SCD in the prospective population-based Rotterdam Study. The study population consisted of 5974 European ancestry subjects, aged 55 years and older, genotyped on Illumina arrays. SCD was defined according to European Society of Cardiology guidelines. Smoking, body mass index, diabetes mellitus, hypertension, heart failure and myocardial infarction were used as covariates in Cox proportional hazard models. Results were combined with reported evidence using inverse-variance weighted meta-analysis. Two hundred and eight (109 witnessed) cases of SCD occurred during a mean follow-up of 10.4 years. Within the Rotterdam Study alone, no significant associations were observed. Upon pooling of results with existing data, we observed strengthening of existing evidence for rs16847549 (US data HR = 1.31, P = 0.0024; Rotterdam Study HR = 1.18, P = 0.16; joint HR = 1.26, P = 0.0011). When the case definition in the Rotterdam Study was restricted to witnessed SCD, association of rs16847549 with SCD became stronger (joint P = 0.00019) and additionally the association between rs12567209 and SCD gained significance (US data HR = 0.57, P = 0.0035; Rotterdam Study HR = 0.69, P = 0.23; joint HR = 0.60, P = 0.0018). In conclusion, this study provided additional evidence for association between genetic variation within NOS1AP and SCD. The mechanism by which this effect is exerted remains to be elucidated.