Background and Aims It is not clear how a polygenic risk score (PRS) can be best combined with guideline-recommended tools for cardiovascular disease (CVD) risk prediction, e.g. SCORE2. Methods A PRS for coronary artery disease (CAD) was calculated in participants of UK Biobank (n = 432 981). Within each tenth of the PRS distribution, the odds ratios (ORs)—referred to as PRS-factor—for CVD (i.e. CAD or stroke) were compared between the entire population and subgroups representing the spectrum of clinical risk. Replication was performed in the combined Framingham/Atherosclerosis Risk in Communities (ARIC) populations (n = 10 757). The clinical suitability of a multiplicative model ‘SCORE2 × PRS-factor’ was tested by risk reclassification. Results In subgroups with highly different clinical risks, CVD ORs were stable within each PRS tenth. SCORE2 and PRS showed no significant interactive effects on CVD risk, which qualified them as multiplicative factors: SCORE2 × PRS-factor = total risk. In UK Biobank, the multiplicative model moved 9.55% of the intermediate (n = 145 337) to high-risk group increasing the individuals in this category by 56.6%. Incident CVD occurred in 8.08% of individuals reclassified by the PRS-factor from intermediate to high risk, which was about two-fold of those remained at intermediate risk (4.08%). Likewise, the PRS-factor shifted 8.29% of individuals from moderate to high risk in Framingham/ARIC. Conclusions This study demonstrates that absolute CVD risk, determined by a clinical risk score, and relative genetic risk, determined by a PRS, provide independent information. The two components may form a simple multiplicative model improving precision of guideline-recommended tools in predicting incident CVD.

中文翻译：

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将多基因评分纳入心血管疾病指南推荐的预测中

背景和目标 目前尚不清楚多基因风险评分 (PRS) 如何与指南推荐的心血管疾病 (CVD) 风险预测工具（例如 SCORE2）最好地结合起来。方法 计算英国生物银行参与者 (n = 432 981) 的冠状动脉疾病 (CAD) PRS。在 PRS 分布的十分之一内，对整个人群和代表临床风险范围的亚组之间的 CVD（即 CAD 或中风）的比值比 (OR)（称为 PRS 因子）进行比较。在弗雷明汉/社区动脉粥样硬化风险 (ARIC) 人群中进行复制（n = 10 757）。通过风险重新分类来测试乘法模型“SCORE2 × PRS 因子”的临床适用性。结果 在临床风险差异很大的亚组中，CVD OR 稳定在 PRS 的十分之一内。 SCORE2 和 PRS 对 CVD 风险没有显着的交互影响，这将它们视为乘法因子：SCORE2 × PRS 因子 = 总风险。在英国生物银行，乘法模型将 9.55% 的中间人群 (n = 145 337) 移至高风险组，使该类别中的个体增加了 56.6%。根据 PRS 因素从中风险重新分类为高风险的个体中，有 8.08% 的人发生了 CVD 事件，约为中风险个体 (4.08%) 的两倍。同样，在 Framingham/ARIC 中，PRS 因子将 8.29% 的个体从中度风险转变为高风险。结论 本研究表明，由临床风险评分确定的绝对 CVD 风险和由 PRS 确定的相对遗传风险提供了独立信息。这两个组件可以形成一个简单的乘法模型，提高指南推荐工具预测 CVD 事件的精度。