Background:There is considerable interest in whether genetic data can be used to improve standard cardiovascular disease risk calculators, as the latter are routinely used in clinical practice to manage preventative treatment.Methods:Using the UK Biobank resource, we developed our own polygenic risk score for coronary artery disease (CAD). We used an additional 60 000 UK Biobank individuals to develop an integrated risk tool (IRT) that combined our polygenic risk score with established risk tools (either the American Heart Association/American College of Cardiology pooled cohort equations [PCE] or UK QRISK3), and we tested our IRT in an additional, independent set of 186 451 UK Biobank individuals.Results:The novel CAD polygenic risk score shows superior predictive power for CAD events, compared with other published polygenic risk scores, and is largely uncorrelated with PCE and QRISK3. When combined with PCE into an IRT, it has superior predictive accuracy. Overall, 10.4% of incident CAD cases were misclassified as low risk by PCE and correctly classified as high risk by the IRT, compared with 4.4% misclassified by the IRT and correctly classified by PCE. The overall net reclassification improvement for the IRT was 5.9% (95% CI, 4.7–7.0). When individuals were stratified into age-by-sex subgroups, the improvement was larger for all subgroups (range, 8.3%–15.4%), with the best performance in 40- to 54-year-old men (15.4% [95% CI, 11.6–19.3]). Comparable results were found using a different risk tool (QRISK3) and also a broader definition of cardiovascular disease. Use of the IRT is estimated to avoid up to 12 000 deaths in the United States over a 5-year period.Conclusions:An IRT that includes polygenic risk outperforms current risk stratification tools and offers greater opportunity for early interventions. Given the plummeting costs of genetic tests, future iterations of CAD risk tools would be enhanced with the addition of a person’s polygenic risk.

中文翻译：

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集成多基因工具显着增强冠状动脉疾病预测

背景：人们对遗传数据是否可用于改进标准心血管疾病风险计算器具有相当大的兴趣，因为后者在临床实践中常规用于管理预防性治疗。方法：使用英国生物银行资源，我们开发了自己的多基因风险评分用于冠状动脉疾病 (CAD)。我们使用了另外 60,000 名英国生物银行个人来开发一个综合风险工具 (IRT)，该工具将我们的多基因风险评分与已建立的风险工具（美国心脏协会/美国心脏病学会汇集队列方程 [PCE] 或英国 QRISK3）相结合，我们在另外一组独立的 186 451 名英国生物银行个体中测试了我们的 IRT。结果：与其他已发表的多基因风险评分相比，新的 CAD 多基因风险评分显示出对 CAD 事件的更好预测能力，并且在很大程度上与 PCE 和 QRISK3 无关。当与 PCE 结合到 IRT 中时，它具有出色的预测准确性。总体而言，10.4% 的 CAD 病例被 PCE 错误归类为低风险，而 IRT 正确归类为高风险，而 IRT 错误归类为 4.4%，PCE 正确归类为 4.4%。IRT 的总体净重新分类改进为 5.9%（95% CI，4.7-7.0）。当个体被按性别划分为亚组时，所有亚组的改善都更大（范围，8.3%–15.4%），40 至 54 岁的男性表现最好（15.4% [95% CI ，11.6-19.3]）。使用不同的风险工具（QRISK3）和更广泛的心血管疾病定义发现了可比较的结果。据估计，在美国使用 IRT 在 5 年内可避免多达 12 000 人死亡。结论：包含多基因风险的 IRT 优于当前的风险分层工具，并为早期干预提供了更大的机会。鉴于基因测试的成本直线下降，未来 CAD 风险工具的迭代将随着一个人的多基因风险的增加而得到增强。