Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
Office of Biostatistics Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
PLoS One. 2020 Nov 13;15(11):e0230035. doi: 10.1371/journal.pone.0230035. eCollection 2020.
Genome-wide association studies have identified multiple genomic loci associated with coronary artery disease, but most are common variants in non-coding regions that provide limited information on causal genes and etiology of the disease. To overcome the limited scope that common variants provide, we focused our investigation on low-frequency and rare sequence variations primarily residing in coding regions of the genome.
Using samples of individuals of European ancestry from ten cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, both cross-sectional and prospective analyses were conducted to examine associations between genetic variants and myocardial infarction (MI), coronary heart disease (CHD), and all-cause mortality following these events. For prevalent events, a total of 27,349 participants of European ancestry, including 1831 prevalent MI cases and 2518 prevalent CHD cases were used. For incident cases, a total of 55,736 participants of European ancestry were included (3,031 incident MI cases and 5,425 incident CHD cases). There were 1,860 all-cause deaths among the 3,751 MI and CHD cases from six cohorts that contributed to the analysis of all-cause mortality. Single variant and gene-based analyses were performed separately in each cohort and then meta-analyzed for each outcome. A low-frequency intronic variant (rs988583) in PLCL1 was significantly associated with prevalent MI (OR = 1.80, 95% confidence interval: 1.43, 2.27; P = 7.12 × 10-7). We conducted gene-based burden tests for genes with a cumulative minor allele count (cMAC) ≥ 5 and variants with minor allele frequency (MAF) < 5%. TMPRSS5 and LDLRAD1 were significantly associated with prevalent MI and CHD, respectively, and RC3H2 and ANGPTL4 were significantly associated with incident MI and CHD, respectively. No loci were significantly associated with all-cause mortality following a MI or CHD event.
This study identified one known locus (ANGPTL4) and four new loci (PLCL1, RC3H2, TMPRSS5, and LDLRAD1) associated with cardiovascular disease risk that warrant further investigation.
全基因组关联研究已经确定了多个与冠状动脉疾病相关的基因组位点，但大多数都是非编码区域的常见变异，这些变异提供的关于疾病的因果基因和病因的信息有限。为了克服常见变异提供的有限范围，我们将研究重点放在主要位于基因组编码区域的低频和罕见序列变异上。
使用来自基因与心血管疾病遗传流行病学（CHARGE）联盟十个队列的欧洲血统个体样本，进行了横断面和前瞻性分析，以研究遗传变异与心肌梗死（MI）、冠心病（CHD）和这些事件后的全因死亡率之间的关系。对于现患事件，共使用了 27349 名欧洲血统的参与者，包括 1831 例现患 MI 病例和 2518 例现患 CHD 病例。对于新发事件，共纳入了 55736 名欧洲血统的参与者（3031 例新发 MI 病例和 5425 例新发 CHD 病例）。来自六个为全因死亡率分析做出贡献的队列的 3751 例 MI 和 CHD 病例中有 1860 例发生了全因死亡。在每个队列中分别进行了单变体和基于基因的分析，然后对每个结果进行了荟萃分析。PLCL1 中的一个低频内含子变异（rs988583）与现患 MI 显著相关（OR = 1.80，95%置信区间：1.43，2.27；P = 7.12×10-7）。我们对累积次要等位基因数（cMAC）≥5 的基因和次要等位基因频率（MAF）<5%的变体进行了基于基因的负担测试。TMPRSS5 和 LDLRAD1 分别与现患 MI 和 CHD 显著相关，RC3H2 和 ANGPTL4 分别与新发 MI 和 CHD 显著相关。没有位点与 MI 或 CHD 事件后的全因死亡率显著相关。
本研究确定了一个已知的位点（ANGPTL4）和四个新的位点（PLCL1、RC3H2、TMPRSS5 和 LDLRAD1）与心血管疾病风险相关，值得进一步研究。
