Aims To construct a polygenic risk score (PRS) for coronary artery disease (CAD) and comprehensively evaluate its potential in clinical utility for primary prevention in Chinese populations. Methods and results Using meta-analytic approach and large genome-wide association results for CAD and CAD-related traits in East Asians, a PRS comprising 540 genetic variants was developed in a training set of 2800 patients with CAD and 2055 controls, and was further assessed for risk stratification for CAD integrating with the guideline-recommended clinical risk score in large prospective cohorts comprising 41 271 individuals. During a mean follow-up of 13.0 years, 1303 incident CAD cases were identified. Individuals with high PRS (the highest 20%) had about three-fold higher risk of CAD than the lowest 20% (hazard ratio 2.91, 95% confidence interval 2.43–3.49), with the lifetime risk of 15.9 and 5.8%, respectively. The addition of PRS to the clinical risk score yielded a modest yet significant improvement in C-statistic (1%) and net reclassification improvement (3.5%). We observed significant gradients in both 10-year and lifetime risk of CAD according to the PRS within each clinical risk strata. Particularly, when integrating high PRS, intermediate clinical risk individuals with uncertain clinical decision for intervention would reach the risk levels (10-year of 4.6 vs. 4.8%, lifetime of 17.9 vs. 16.6%) of high clinical risk individuals with intermediate (20–80%) PRS. Conclusion The PRS could stratify individuals into different trajectories of CAD risk, and further refine risk stratification for CAD within each clinical risk strata, demonstrating a great potential to identify high-risk individuals for targeted intervention in clinical utility. Key question Key finding Take-home message The incorporation of polygenic risk into clinical care setting may provide a valuable risk stratification guidance to identify high-risk individuals for targeted intervention in primary prevention of CAD.

ObjectiveTo examine whether adherence to ideal cardiovascular health (CVH) can mitigate the genetic risk of coronary artery disease (CAD) in non-European populations.MethodsFine and Grey’s models were used to calculate HRs and their corresponding 95% CIs, as well as the lifetime risk of CVH metrics across Polygenic Risk Score (PRS) categories.ResultsWe included 39 755 individuals aged 30–75 years in Chinese prospective cohorts. 1275 CAD cases were recorded over a mean follow-up of 12.9 years. Compared with unfavourable CVH profile (zero to three ideal CVH metrics), favourable CVH profile (six to seven ideal CVH metrics) demonstrated similar relative effects across PRS categories, with the HRs of 0.40 (95% CI 0.24 to 0.67), 0.41 (95% CI 0.32 to 0.52) and 0.36 (95% CI 0.26 to 0.52) in low (bottom quintile of PRS), intermediate (two to four quintiles of PRS) and high (top quintile of PRS) PRS categories, respectively. For the absolute risk reduction (ARR), individuals with high PRS achieved the greatest benefit from favourable CVH, mitigating the risk to the average level of population (from 21.1% to 8.7%), and the gradient was strengthened in individuals at the top 5% of PRS. Moreover, compared with individuals at low PRS, those at high PRS obtained longer CAD-free years (2.6 vs 1.1) from favourable CVH at the index age of 35 years.ConclusionFavourable CVH profile reduced the CAD relative risk by similar magnitude across PRS categories, while the ARR from favourable CVH was most pronounced in high PRS category. Attaining favourable CVH should be encouraged for all individuals, especially in individuals with high genetic susceptibility.

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Background: Familial hypercholesterolemia (FH) is underrecognized, and its association with coronary artery disease (CAD) remains limited, especially in China. We aimed to investigate the prevalence of FH and its relationship with CAD in a large Chinese cohort. Methods: FH was defined using the Make Early Diagnosis to Prevent Early Death (MEDPED) criteria. The crude and age-sex standardized prevalence of FH were calculated based on surveys of the Prediction for Atherosclerotic Cardiovascular Disease Risk in China (China-PAR) project during 2007−2008. The associations of FH with incident CAD and its major subtypes were estimated with the cohort-stratified multivariate Cox proportional hazard models based on the data from the baseline to the last follow-up (2018−2020).