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Meta-Analysis
. 2022 May 7;43(18):1702-1711.
doi: 10.1093/eurheartj/ehac093.

A polygenic risk score improves risk stratification of coronary artery disease: a large-scale prospective Chinese cohort study

Xiangfeng Lu  1 , Zhongying Liu  1 , Qingmei Cui  1 , Fangchao Liu  1 , Jianxin Li  1 , Xiaoge Niu  1 , Chong Shen  2 , Dongsheng Hu  3   4 , Keyong Huang  1 , Jichun Chen  1 , Xiaolong Xing  1 , Yingxin Zhao  5 , Fanghong Lu  5 , Xiaoqing Liu  6 , Jie Cao  1 , Shufeng Chen  1 , Hongxia Ma  2 , Ling Yu  7 , Xianping Wu  8 , Xigui Wu  1 , Ying Li  1 , Huan Zhang  9 , Xingbo Mo  9 , Liancheng Zhao  1 , Jianfeng Huang  1 , Laiyuan Wang  1 , Wanqing Wen  10 , Xiao-Ou Shu  10 , Fumihiko Takeuchi  11 , Woon-Puay Koh  12 , E Shyong Tai  13   14 , Ching-Yu Cheng  15 , Tien Yin Wong  15   16 , Xuling Chang  17   18 , Mark Yan-Yee Chan  19   20 , Wei Gao  21 , Hong Zheng  22 , Kexin Chen  22 , Jing Chen  23 , Jiang He  24 , Clara Sze-Man Tang  25 , Karen Siu Ling Lam  26 , Hung-Fat Tse  26 , Chloe Yu Yan Cheung  26 , Atsushi Takahashi  27   28 , Michiaki Kubo  27 , Norihiro Kato  11 , Chikashi Terao  27 , Yoichiro Kamatani  27   29 , Pak Chung Sham  30 , Chew-Kiat Heng  17 , Zhibin Hu  2 , Y Eugene Chen  31 , Tangchun Wu  32 , Hongbing Shen  2 , Cristen J Willer  31   33 , Dongfeng Gu  1
Affiliations
Meta-Analysis

A polygenic risk score improves risk stratification of coronary artery disease: a large-scale prospective Chinese cohort study

Xiangfeng Lu et al. Eur Heart J. .

Abstract

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.

Keywords: Clinical risk score; Coronary artery disease; Polygenic risk score.

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Figures

Structured Graphical Abstract
Structured Graphical Abstract
The polygenic risk has a great potential to refine CAD risk stratification within each guideline-recommended clinical risk category and inform clinical decision making for primary prevention. Among individuals at intermediate clinical risk whose guideline-based recommendations are unclear, those with high polygenic risk should be recommended to initiate lifestyle and pharmacological intervention. Individuals with both high polygenic risk and high clinical risk urgently need intensive prevention. Combination of polygenic risk and clinical risk could promote precision prevention of CAD and reduce the disease burden, particularly considering inadequate primary prevention or statins and antihypertensive treatment in China.
Figure 1
Figure 1
Flow chart of the study. (A) Derivation of metaPRS for CAD in training dataset. (B) Validation of metaPRS in prospective cohorts. PRS, polygenic risk score; CAD, coronary artery disease; BP, blood pressure; BMI, body mass index; T2D, type 2 diabetes; TC, total cholesterol; LDL-C, LDL cholesterol; HDL-C, HDL cholesterol; TG, triglycerides.
Figure 2
Figure 2
Cumulative incidence curves for incident coronary artery disease across polygenic risk categories. Fine and Gray’s proportional hazards model accounting for competing risk was used to estimate the hazard ratios (95% confidence intervals) and the cumulative risk of coronary artery disease adjusted for sex and the first four principal components with age as the time scale. Polygenic risk categories: low (bottom quintile), intermediate (2nd–4th quintile), or high (top quintile) risk according to quintiles of the metaPRS. CAD, coronary artery disease; HR, hazard ratio; CI, confidence interval.
Figure 3
Figure 3
Ten-year and lifetime risk of coronary artery disease according to clinical and polygenic risk categories. (A) Ten-year risk of coronary artery disease obtained from the recalibrated clinical risk and metaPRS model with follow-up time as the time scale. (B) Lifetime risk of coronary artery disease (till 80 years of age) obtained from the recalibrated clinical risk and metaPRS model accounting for competing risk with age as the time scale. Participants were stratified into low (<2.5%), intermediate (2.5–4.4%), high (4.5–5.9%), and very high (≥6%) 10-year risk of CAD categories, approximately equating to the atherosclerotic cardiovascular disease risk of <5, 5–9.9, 10–14.9, and ≥15%. According to the risk assessment guideline from China, the established treatment threshold for atherosclerotic cardiovascular disease is the 10-year risk of atherosclerotic cardiovascular disease of 10%. CAD, coronary artery disease; ASCVD, atherosclerotic cardiovascular disease; PRS, polygenic risk score.
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