Genome-wide and phenome-wide analysis of ideal cardiovascular health in the VA Million Veteran Program.
Genome-wide and phenome-wide analysis of ideal cardiovascular health in the VA Million Veteran Program.
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DOI：
10.1371/journal.pone.0267900
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发表时间：
2022
期刊：
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
遗传学研究可能有助于确定因果通路;因此，我们试图确定理想CVH的遗传决定因素及其与多人群退伍军人管理局百万退伍军人计划中CVD结果的相关性。根据基线时确定的3个临床因素（血压、总胆固醇和血糖水平）和3个行为因素（吸烟状况、体力活动和BMI）计算理想健康评分（IHS）。多人群全基因组关联研究（GWAS）分别使用线性和logistic回归对IHS和二元理想健康进行。使用来自IHS GWAS的全基因组显著SNP，我们创建了加权IHS多基因风险评分（PRSIHS），用于（i）进行PRSIHS和ICD-9表型之间关联的全表型关联研究（PheWAS），以及（ii）使用logistic和考克斯回归进一步测试与死亡率和选定CVD结局的关联，并作为孟德尔随机化的工具变量。发现和复制队列分别由142，404名（119，129名欧洲裔美国人（EUR）; 16，495名非洲裔美国人（AFR））和45，766名（37，646欧元; 5，366 AFR）参与者组成。平均年龄为65.8岁（SD = 11.2），92.7%为男性。总的来说，4.2%的人表现出基于临床和行为因素的理想CVH。在多人群荟萃分析中，17个位点的变异与IHS相关，每个位点都与IHS的多个组分具有已知的GWAS关联。PheWAS对456，026名参与者的分析显示，PRSIHS增加与许多CVD结局和风险因素的比值比降低相关。理想CVH的IHS和PRSIHS指标均与CVD结局和CVD死亡率显著降低相关。一组高度关注的遗传变异有助于在美国退伍军人的多种族队列中存在理想的CVH。受遗传影响的理想CVH与较低的CVD结局和死亡率相关。
Genetic studies may help identify causal pathways; therefore, we sought to identify genetic determinants of ideal CVH and their association with CVD outcomes in the multi-population Veteran Administration Million Veteran Program. An ideal health score (IHS) was calculated from 3 clinical factors (blood pressure, total cholesterol, and blood glucose levels) and 3 behavioral factors (smoking status, physical activity, and BMI), ascertained at baseline. Multi-population genome-wide association study (GWAS) was performed on IHS and binary ideal health using linear and logistic regression, respectively. Using the genome-wide significant SNPs from the IHS GWAS, we created a weighted IHS polygenic risk score (PRSIHS) which was used (i) to conduct a phenome-wide association study (PheWAS) of associations between PRSIHS and ICD-9 phenotypes and (ii) to further test for associations with mortality and selected CVD outcomes using logistic and Cox regression and, as an instrumental variable, in Mendelian Randomization. The discovery and replication cohorts consisted of 142,404 (119,129 European American (EUR); 16,495 African American (AFR)), and 45,766 (37,646 EUR; 5,366 AFR) participants, respectively. The mean age was 65.8 years (SD = 11.2) and 92.7% were male. Overall, 4.2% exhibited ideal CVH based on the clinical and behavioral factors. In the multi-population meta-analysis, variants at 17 loci were associated with IHS and each had known GWAS associations with multiple components of the IHS. PheWAS analysis in 456,026 participants showed that increased PRSIHS was associated with a lower odds ratio for many CVD outcomes and risk factors. Both IHS and PRSIHS measures of ideal CVH were associated with significantly less CVD outcomes and CVD mortality. A set of high interest genetic variants contribute to the presence of ideal CVH in a multi-ethnic cohort of US Veterans. Genetically influenced ideal CVH is associated with lower odds of CVD outcomes and mortality.
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