Background:Polygenic risk scores (PRSs) are associated with coronary artery disease (CAD), but the clinical potential of using PRSs at the single-patient level for risk stratification has yet to be established. We investigated whether adding a PRS to clinical risk factors (CRFs) improves risk stratification in patients referred to coronary computed tomography angiography on a suspicion of obstructive CAD.Methods:In this prespecified diagnostic substudy of the Dan-NICAD trial (Danish study of Non-Invasive testing in Coronary Artery Disease), we included 1617 consecutive patients with stable chest symptoms and no history of CAD referred for coronary computed tomography angiography. CRFs used for risk stratification were age, sex, symptoms, prior or active smoking, antihypertensive treatment, lipid-lowering treatment, and diabetes. In addition, patients were genotyped, and their PRSs were calculated. All patients underwent coronary computed tomography angiography. Patients with a suspected ≥50% stenosis also underwent invasive coronary angiography with fractional flow reserve. A combined end point of obstructive CAD was defined as a visual invasive coronary angiography stenosis >90%, fractional flow reserve <0.80, or a quantitative coronary analysis stenosis >50% if fractional flow reserve measurements were not feasible.Results:The PRS was associated with obstructive CAD independent of CRFs (adjusted odds ratio, 1.8 [95% CI, 1.5–2.2] per SD). The PRS had an area under the curve of 0.63 (0.59–0.68), which was similar to that for age and sex. Combining the PRS with CRFs led to a CRF+PRS model with area under the curve of 0.75 (0.71–0.79), which was 0.04 more than the CRF model (P=0.0029). By using pretest probability (pretest probability) cutoffs at 5% and 15%, a net reclassification improvement of 15.8% (P=3.1×10⁻⁴) was obtained, with a down-classification of risk in 24% of patients (211 of 862) in whom the pretest probability was 5% to 15% based on CRFs alone.Conclusions:Adding a PRS improved risk stratification of obstructive CAD beyond CRFs, suggesting a modest clinical potential of using PRSs to guide diagnostic testing in the contemporary clinical setting.Registration:URL: https://www.clinicaltrials.gov; Unique identifier: NCT02264717.

中文翻译：

---

多基因风险评分——稳定性胸痛患者冠状动脉疾病风险分层的增强

背景：多基因风险评分 (PRS) 与冠状动脉疾病 (CAD) 相关，但在单一患者水平上使用 PRS 进行风险分层的临床潜力尚未确定。我们调查了在临床危险因素 (CRF) 中添加 PRS 是否可以改善疑似阻塞性 CAD 患者的风险分层。方法：在 Dan-NICAD 试验（丹麦非冠状动脉疾病的侵入性测试），我们连续纳入了 1617 名胸部症状稳定且无 CAD 病史的患者，这些患者转诊至冠状动脉 CT 血管造影。用于风险分层的 CRF 包括年龄、性别、症状、既往或主动吸烟、抗高血压治疗、降脂治疗和糖尿病。此外，对患者进行基因分型，并计算他们的 PRS。所有患者均行冠状动脉计算机断层扫描血管造影。疑似 ≥50% 狭窄的患者也接受了血流储备分数的侵入性冠状动脉造影。阻塞性 CAD 的综合终点被定义为视觉侵入性冠状动脉造影狭窄 >90%，血流储备分数 <0.80，或如果血流储备分数测量不可行，则定量冠状动脉分析狭窄 >50%。结果：PRS 与患有独立于 CRF 的阻塞性 CAD（调整优势比，1.8 [95% CI，1.5-2.2]/SD）。PRS 的曲线下面积为 0.63（0.59-0.68），与年龄和性别相似。将 PRS 与 CRF 相结合得到 CRF+PRS 模型，其曲线下面积为 0.75（0.71-0.79），比 CRF 模型多 0.04（P = 0.0029)。通过使用 5% 和 15% 的预测试概率（预测试概率）截止值，获得了 15.8% 的净重新分类改进（P = 3.1×10 ^-4），24% 的患者（211 862），其中仅基于 CRF 的预测概率为 5% 至 15%。结论：添加 PRS 改善了 CRF 以外的阻塞性 CAD 的风险分层，表明在当代临床环境中使用 PRS 指导诊断测试具有适度的临床潜力。注册：网址：https://www.clinicaltrials.gov；唯一标识符：NCT02264717。