Polygenic Risk Score-enhanced Risk Stratification of Coronary Artery Disease in Patients with Stable Chest Pain

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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 (CTA) on a suspicion of obstructive CAD. Methods - In this prespecified diagnostic substudy of the Dan-NICAD trial we included 1617 consecutive patients with stable chest symptoms and no prior history of CAD referred for coronary CTA. 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 CTA. Patients with a suspected ≥50% stenosis also underwent invasive coronary angiography (ICA) with fractional flow reserve (FFR). A combined endpoint of obstructive CAD was defined as a visual ICA stenosis >90%, FFR <0.80, or a quantitative coronary analysis stenosis >50% if FFR measurements were not feasible. Results - The PRS was associated with obstructive CAD independent of CRFs (adjusted OR 1.8 [95%CI 1.5-2.2] per SD). The PRS had an area under the curve (AUC) 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 AUC of 0.75 (0.71-0.79), which was 0.04 more than the CRF model (P=0.0029). By using pre-test probability (PTP) cutoffs at 5% and 15%, a net reclassification improvement of 15.8% (P=3.1e-4) was obtained, with a down-classification of risk in 24% of patients (211/862) in whom the PTP was 5%-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.

TidsskriftCirculation. Genomic and precision medicine
Sider (fra-til)323-330
Antal sider8
StatusUdgivet - jun. 2021

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