对 480,000 名成年人的冠心病的基因组风险预测：对一级预防的影响。
Genomic Risk Prediction of Coronary Artery Disease in 480,000 Adults: Implications for Primary Prevention.
机构信息
Cambridge Baker Systems Genomics Initiative, Melbourne, Victoria, Australia, and Cambridge, United Kingdom; Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia; MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; Department of Clinical Pathology and School of BioSciences, University of Melbourne, Parkville, Victoria, Australia; The Alan Turing Institute, London, United Kingdom.
Cambridge Baker Systems Genomics Initiative, Melbourne, Victoria, Australia, and Cambridge, United Kingdom; Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia; MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; Department of Clinical Pathology and School of BioSciences, University of Melbourne, Parkville, Victoria, Australia.
出版信息
J Am Coll Cardiol. 2018 Oct 16;72(16):1883-1893. doi: 10.1016/j.jacc.2018.07.079.
BACKGROUND
Coronary artery disease (CAD) has substantial heritability and a polygenic architecture. However, the potential of genomic risk scores to help predict CAD outcomes has not been evaluated comprehensively, because available studies have involved limited genomic scope and limited sample sizes.
OBJECTIVES
This study sought to construct a genomic risk score for CAD and to estimate its potential as a screening tool for primary prevention.
METHODS
Using a meta-analytic approach to combine large-scale, genome-wide, and targeted genetic association data, we developed a new genomic risk score for CAD (metaGRS) consisting of 1.7 million genetic variants. We externally tested metaGRS, both by itself and in combination with available data on conventional risk factors, in 22,242 CAD cases and 460,387 noncases from the UK Biobank.
RESULTS
The hazard ratio (HR) for CAD was 1.71 (95% confidence interval [CI]: 1.68 to 1.73) per SD increase in metaGRS, an association larger than any other externally tested genetic risk score previously published. The metaGRS stratified individuals into significantly different life course trajectories of CAD risk, with those in the top 20% of metaGRS distribution having an HR of 4.17 (95% CI: 3.97 to 4.38) compared with those in the bottom 20%. The corresponding HR was 2.83 (95% CI: 2.61 to 3.07) among individuals on lipid-lowering or antihypertensive medications. The metaGRS had a higher C-index (C = 0.623; 95% CI: 0.615 to 0.631) for incident CAD than any of 6 conventional factors (smoking, diabetes, hypertension, body mass index, self-reported high cholesterol, and family history). For men in the top 20% of metaGRS with >2 conventional factors, 10% cumulative risk of CAD was reached by 48 years of age.
CONCLUSIONS
The genomic score developed and evaluated here substantially advances the concept of using genomic information to stratify individuals with different trajectories of CAD risk and highlights the potential for genomic screening in early life to complement conventional risk prediction.
背景
冠心病（CAD）具有显著的遗传性和多基因结构。然而，基因组风险评分在预测 CAD 结局方面的潜力尚未得到全面评估，因为现有研究的基因组范围有限，样本量也有限。
目的
本研究旨在构建 CAD 的基因组风险评分，并评估其作为初级预防筛查工具的潜力。
方法
采用荟萃分析方法结合大规模全基因组和靶向遗传关联数据，我们开发了一种新的 CAD 基因组风险评分（metaGRS），由 170 万个遗传变异组成。我们在 UK Biobank 中对 22242 例 CAD 病例和 460387 例非病例进行了 metaGRS 的外部测试，分别单独和结合常规危险因素数据进行了测试。
结果
metaGRS 每增加 1 个标准差，CAD 的危险比（HR）为 1.71（95%置信区间[CI]：1.68 至 1.73），这一关联大于之前发表的任何其他经过外部测试的遗传风险评分。metaGRS 将个体分为明显不同的 CAD 风险生命轨迹，metaGRS 分布在前 20%的个体的 HR 为 4.17（95%CI：3.97 至 4.38），而分布在后 20%的个体的 HR 为 2.83（95%CI：2.61 至 3.07）。在服用降脂或降压药物的个体中，metaGRS 的 HR 为 2.33（95%CI：2.14 至 2.54）。metaGRS 对 CAD 发病的 C 指数（C = 0.623；95%CI：0.615 至 0.631）高于任何 6 项常规因素（吸烟、糖尿病、高血压、体重指数、自述高胆固醇和家族史）。在 metaGRS 排名前 20%的男性中，如果有超过 2 个常规因素，其 10%的 CAD 累积风险将在 48 岁时达到。
结论
这里开发和评估的基因组评分极大地推进了利用基因组信息对具有不同 CAD 风险轨迹的个体进行分层的概念，并突出了基因组筛查在早期生活中补充传统风险预测的潜力。
Zotero 插件