Background:Understanding the predictive utility of previously derived polygenic risk scores (PRSs) for long-term risk of coronary heart disease (CHD) and its additive value beyond traditional risk factors can inform prevention strategies.Methods:Data from adults 20 to 59 years of age who were free of CHD from the FOS (Framingham Offspring Study) and the ARIC (Atherosclerosis Risk in Communities) study were analyzed. Because the PRS was derived from samples of predominantly European ancestry, individuals who self-reported White race were included. The sample was stratified by age and cohort: young (FOS, 20–39 years [median, 30 years] of age), early midlife (FOS, 40–59 years [median, 43] years of age), and late midlife (ARIC, 45–59 years [median, 52 years] of age). Two previously derived and validated prediction tools were applied: (1) a 30-year traditional risk factor score and (2) a genome-wide PRS comprising >6 million genetic variants. Hazard ratios for the association between each risk estimate and incident CHD were calculated. Predicted and observed rates of CHD were compared to assess discrimination for each model individually and together with the optimism-corrected C index (95% CI).Results:Among 9757 participants, both the traditional risk factor score (hazard ratio per 1 SD, 2.60 [95% CI, 2.08–3.27], 2.09 [95% CI, 1.83–2.40], and 2.11 [95% CI, 1.96–2.28]) and the PRS (hazard ratio, 1.98 [95% CI, 1.70–2.30], 1.64 [95% CI, 1.47–1.84], and 1.22 [95% CI, 1.15–1.30]) were significantly associated with incident CHD in young, early midlife, and late midlife, respectively. Discrimination was similar or better for the traditional risk factor score (C index, 0.74 [95% CI, 0.70–0.78], 0.70 [95% CI, 0.67–0.72], and 0.72 [95% CI, 0.70–0.73]) compared with an age- and sex-adjusted PRS (0.73 [95% CI, 0.69–0.78], 0.66 [95% CI, 0.62–0.69], and 0.66 [95% CI, 0.64–0.67]) in young, early-midlife, and late-midlife participants, respectively. The ΔC index when PRS was added to the traditional risk factor score was 0.03 (95% CI, 0.001–0.05), 0.02 (95% CI, −0.002 to 0.037), and 0.002 (95% CI, −0.002 to 0.006) in young, early-midlife, and late-midlife participants, respectively.Conclusions:Despite a statistically significant association between PRS and 30-year risk of CHD, the C statistic improved only marginally with the addition of PRS to the traditional risk factor model among young adults and did not improve among midlife adults. PRS, an immutable factor that cannot be directly intervened on, has minimal clinical utility for long-term CHD prediction when added to a traditional risk factor model.

中文翻译：

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经验证的多基因风险评分对中青年冠心病长期风险的预测效用


背景：了解先前得出的多基因风险评分 (PRS) 对冠心病 (CHD) 长期风险的预测效用及其超越传统风险因素的附加价值可以为预防策略提供信息。方法：来自 20 至 59 岁成年人的数据对 FOS（弗雷明汉后代研究）和 ARIC（社区动脉粥样硬化风险）研究中未患冠心病的年龄进行了分析。由于 PRS 源自主要是欧洲血统的样本，因此自我报告的白人种族的个体也被包括在内。样本按年龄和队列进行分层：年轻（FOS，20-39 岁[中位数，30 岁]）、中年早期（FOS，40-59 岁[中位数，43] 岁）和中年晚期（FOS，40-59 岁[中位数，43] 岁）。 ARIC，45-59 岁[中位年龄 52 岁]）。应用了两种先前导出并经过验证的预测工具：(1) 30 年传统风险因素评分和 (2) 包含超过 600 万个遗传变异的全基因组 PRS。计算了每个风险估计与冠心病事件之间关联的风险比。对 CHD 的预测率和观察率进行比较，以单独评估每个模型的歧视性并结合乐观校正 C 指数 (95% CI)。 结果：在 9757 名参与者中，传统风险因素评分（每 1 个 SD 的风险比为 2.60） [95% CI, 2.08–3.27]、2.09 [95% CI, 1.83–2.40] 和 2.11 [95% CI, 1.96–2.28]）和 PRS（风险比，1.98 [95% CI, 1.70–2.30]） 、1.64 [95% CI, 1.47–1.84] 和 1.22 [95% CI, 1.15–1.30]）分别与年轻、中年早期和中年晚期的 CHD 事件显着相关。传统风险因素评分的区分度相似或更好（C 指数，0.74 [95% CI，0.70–0.78]、0.70 [95% CI，0.67–0.72] 和 0.72 [95% CI，0.70–0]。73]）与年龄和性别调整的 PRS（0.73 [95% CI，0.69–0.78]、0.66 [95% CI，0.62–0.69] 和 0.66 [95% CI，0.64–0.67]）相比，在年轻人中，分别是中年早期和中年晚期的参与者。将 PRS 添加到传统危险因素评分中时的 ΔC 指数分别为 0.03（95% CI，0.001-0.05）、0.02（95% CI，-0.002 至 0.037）和 0.002（95% CI，-0.002 至 0.006）。分别为年轻、中年早期和中年晚期参与者。 结论：尽管 PRS 与 30 年冠心病风险之间存在统计显着相关性，但在年轻人中，将 PRS 添加到传统风险因素模型后，C 统计数据仅略有改善成年人中，中年成年人中没有改善。 PRS 是一种无法直接干预的不可变因素，当添加到传统的危险因素模型中时，其对于长期 CHD 预测的临床效用很小。