Cardiovascular disease (CVD) is responsible for 31% of all deaths worldwide. Among CVD risk factors are age, race, increased systolic blood pressure (BP), and dyslipidemia. Both BP and blood lipids levels change with age, with a dose-dependent relationship between the cumulative exposure to hyperlipidemia and the risk of CVD. We performed an exome sequence association study using longitudinal data with up to 7805 European Americans (EAs) and 3171 African Americans (AAs) from the Atherosclerosis Risk in Communities (ARIC) study. We assessed associations of common (minor allele frequency > 5%) nonsynonymous and splice-site variants and gene-based sets of rare variants with levels and with longitudinal change of seven CVD risk factor phenotypes (BP traits: systolic BP, diastolic BP, pulse pressure; lipids traits: triglycerides, total cholesterol, high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C]). Furthermore, we investigated the relationship of the identified variants and genes with select CVD endpoints. We identified two novel genes: DCLK3 associated with the change of HDL-C levels in AAs and RAB7L1 associated with the change of LDL-C levels in EAs. RAB7L1 is further associated with an increased risk of heart failure in ARIC EAs. Investigation of the contribution of genetic factors to the longitudinal change of CVD risk factor phenotypes promotes our understanding of the etiology of CVD outcomes, stressing the importance of incorporating the longitudinal structure of the cohort data in future analyses.

中文翻译：

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社区动脉粥样硬化风险研究中欧洲裔美国人和非裔美国人心血管危险因素表型水平和纵向变化的外显子序列关联研究

心血管疾病 (CVD) 导致全球死亡人数的 31%。CVD 危险因素包括年龄、种族、收缩压 (BP) 升高和血脂异常。血压和血脂水平都随着年龄的增长而变化，高脂血症的累积暴露与心血管疾病风险之间存在剂量依赖性关系。我们使用来自社区动脉粥样硬化风险 (ARIC) 研究的多达 7805 名欧洲裔美国人 (EA) 和 3171 名非洲裔美国人 (AA) 的纵向数据进行了外显子组序列关联研究。我们评估了常见（次要等位基因频率 > 5%）非同义和剪接位点变异以及基于基因的罕见变异组与七种 CVD 危险因素表型水平和纵向变化的关联（血压特征：收缩压、舒张压、脉搏）压力；血脂性状：甘油三酯、总胆固醇、高密度脂蛋白胆固醇[HDL-C]、低密度脂蛋白胆固醇[LDL-C]）。此外，我们还研究了已识别的变异和基因与选定的 CVD 终点的关系。我们鉴定了两个新基因：与 AA 中 HDL-C 水平变化相关的DCLK3和与 EA 中 LDL-C 水平变化相关的RAB7L1 。RAB7L1进一步与 ARIC EA 心力衰竭风险增加相关。研究遗传因素对 CVD 危险因素表型纵向变化的贡献促进了我们对 CVD 结果病因学的理解，强调了在未来分析中纳入队列数据纵向结构的重要性。