Predictive Accuracy of a Polygenic Risk Score Compared With a Clinical Risk Score for Incident Coronary Heart Disease
Predictive Accuracy of a Polygenic Risk Score Compared With a Clinical Risk Score for Incident Coronary Heart Disease
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DOI：
10.1001/jama.2019.21782
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发表时间：
2020-02-18
影响因子：
120.7
通讯作者：
Wang, Thomas J.
中科院分区：
文献类型：
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作者：
Mosley, Jonathan D.;Gupta, Deepak K.;Wang, Thomas J.
由数百万个单核苷酸多态(SNPs)组成的多基因风险评分对人群范围的冠心病(CHD)筛查可能是有用的。目的确定与指南推荐的临床风险方程相比，多基因风险评分是否可以改善CHD的预测。设计、设置和参与者从1996年到2015年12月31日，从1996年到2015年12月31日，在4847名年龄在45岁到79岁之间的欧洲白人血统成年人和2390名参与动脉粥样硬化多种族研究(MESA)的成年人中，对先前验证的多基因风险评分的预测准确性进行了回顾性队列研究。多基因风险评分的表现与2013年美国心脏病学会和美国心脏协会合并队列方程的结果进行了比较。每个参与者的遗传风险通过将6 630 149个SNP的体重和等位基因剂量的乘积相加来计算。权重基于一项国际全基因组协会研究。主要结果和指标预测10年内首次发生的CHD事件(包括心肌梗死、致命的冠状动脉事件、无症状的梗塞、血管重建手术或复苏的心脏骤停)使用模型辨别、校准和净重新分类改进(NRI)的测量方法进行评估。结果研究人群包括ARIC研究中的4847名成年人(平均年龄62.9[5.6]岁；56.4%的女性)和2390名来自Mesa队列的成年人(平均[SD]年龄61.8[9.6]岁；52.2%的女性)。发生冠心病事件的参与者分别为696名(14.4%)和227名(9.5%)，平均随访时间分别为15.5年(四分位数范围[IQR]，6.3年)和14.2年(IQR，2.5年)。ARIC的多基因风险评分与10年的CHD发病率显著相关，每增加一个SD的危险比为1.24(95%CI，1.15~1.34)，在MESA为1.38(95%CI，1.21~1.58)。在合并的队列方程中加入多基因风险分数并没有显著增加两个队列中的C统计量(ARIC，C统计量的变化，-0.001；95%CI，-0.009至0.006；MESA，0.021；95%CI，-0.0004至0.043)。在7.5%的10年风险阈值下，在合并的队列方程中加入多基因风险评分并没有在ARIC(NRI，0.018，95%CI，-0.012至0.036)或MESA(NRI，0.001，95%CI，-0.038至0.076)的重新分类方面提供显著改善。结论：在对2个美国成人队列的分析中，多基因风险评分与发生的冠心病事件相关，但与传统预测指标相比，多基因风险评分并未显著改善区分、校正或风险重新分类。这些发现表明，在一般的白人中年人群中，多基因风险评分可能不会增强风险预测。
Importance Polygenic risk scores comprising millions of single-nucleotide polymorphisms (SNPs) could be useful for population-wide coronary heart disease (CHD) screening.Objective To determine whether a polygenic risk score improves prediction of CHD compared with a guideline-recommended clinical risk equation.Design, Setting, and Participants A retrospective cohort study of the predictive accuracy of a previously validated polygenic risk score was assessed among 4847 adults of white European ancestry, aged 45 through 79 years, participating in the Atherosclerosis Risk in Communities (ARIC) study and 2390 participating in the Multi-Ethnic Study of Atherosclerosis (MESA) from 1996 through December 31, 2015, the final day of follow-up. The performance of the polygenic risk score was compared with that of the 2013 American College of Cardiology and American Heart Association pooled cohort equations.Exposures Genetic risk was computed for each participant by summing the product of the weights and allele dosage across 6 630 149 SNPs. Weights were based on an international genome-wide association study.Main Outcomes and Measures Prediction of 10-year first CHD events (including myocardial infarctions, fatal coronary events, silent infarctions, revascularization procedures, or resuscitated cardiac arrest) assessed using measures of model discrimination, calibration, and net reclassification improvement (NRI).Results The study population included 4847 adults from the ARIC study (mean [SD] age, 62.9 [5.6] years; 56.4% women) and 2390 adults from the MESA cohort (mean [SD] age, 61.8 [9.6] years; 52.2% women). Incident CHD events occurred in 696 participants (14.4%) and 227 participants (9.5%), respectively, over median follow-up of 15.5 years (interquartile range [IQR], 6.3 years) and 14.2 (IQR, 2.5 years) years. The polygenic risk score was significantly associated with 10-year CHD incidence in ARIC with hazard ratios per SD increment of 1.24 (95% CI, 1.15 to 1.34) and in MESA, 1.38 (95% CI, 1.21 to 1.58). Addition of the polygenic risk score to the pooled cohort equations did not significantly increase the C statistic in either cohort (ARIC, change in C statistic, -0.001; 95% CI, -0.009 to 0.006; MESA, 0.021; 95% CI, -0.0004 to 0.043). At the 10-year risk threshold of 7.5%, the addition of the polygenic risk score to the pooled cohort equations did not provide significant improvement in reclassification in either ARIC (NRI, 0.018, 95% CI, -0.012 to 0.036) or MESA (NRI, 0.001, 95% CI, -0.038 to 0.076). The polygenic risk score did not significantly improve calibration in either cohort.Conclusions and Relevance In this analysis of 2 cohorts of US adults, the polygenic risk score was associated with incident coronary heart disease events but did not significantly improve discrimination, calibration, or risk reclassification compared with conventional predictors. These findings suggest that a polygenic risk score may not enhance risk prediction in a general, white middle-aged population.