Polygenic Risk Score Modifies Risk of Coronary Artery Disease Conferred by Low-Density Lipoprotein Cholesterol

Abstract

An individual's lifetime risk of Coronary Artery Disease (CAD) is determined by a combination of genetic and lifestyle factors. Whilst adherence to a healthy lifestyle can help individuals with high genetic risk reduce their lifetime risk of CAD, the extent to which blood lipid levels affect CAD risk in individuals with varying genetic risk remains unknown. To explore how genetics, blood lipids and CAD risk interact, we derived a novel genome-wide polygenic risk score (PRS) for CAD. We then applied the PRS to individuals from the UK Biobank and divided them into Low PRS (bottom 10 percentiles of PRS distribution), Intermediate PRS (PRS in the 10th-90th percentiles), and High PRS (top 10 percentiles), and further stratified individuals by blood lipid levels. We found that the elevated CAD risk conferred by high low-density lipoprotein cholesterol (LDL-C) was modified by the interaction with PRS (P-value interaction: <0.005). Individuals with High PRS and whose LDL-C was Borderline (between 130 and 160 mg/dL) had higher CAD relative risk (HR 3.10; 95% CI, 2.55-3.76) than those at Intermediate PRS whose LDL-C were Very High (>190 mg/dL; HR 2.77; 95% CI, 2.33-3.28). Furthermore, individuals with High PRS but whose lipid levels were below the following thresholds did not have a significantly increased risk for incident CAD: LDL-C <130 mg/dL, total Cholesterol (TC) <200 mg/dL, LDL-C:HDL <2.0 and TC:HDL <3.0. In addition, individuals with Low PRS and Very High LDL-C (>190 mg/dl) did not have increased CAD risk, which was comparable to individuals with Intermediate PRS and Optimal LDL-C (<130 mg/dL). Our results have important implications for the primary prevention of coronary artery disease. Currently, healthy individuals with Borderline LDL-C (130-159 mg/dL) are not considered to be at high risk of CAD. Here we demonstrate that the combination of Borderline LDL-C and High PRS results in CAD relative risk which is greater than individuals without high polygenic risk, but whose LDL-C levels are high enough for statins to be recommended (>190 mg/dL). This analysis therefore demonstrates that PRS can identify a proportion of the population who are at high-risk of CAD but who are invisible to current approaches for assessing CAD risk. Moreover, of perhaps greater significance is the evidence that individuals who have a combination of High PRS and Optimal blood lipid levels do not have greater risk of CAD than individuals without high polygenic risk and the same Optimal blood lipid levels. Our results suggest that high polygenic risk for CAD could be overcome by controlling blood lipid levels. We propose that incorporating PRS into CAD risk assessment early in life could allow individuals at high polygenic risk to benefit from tailored blood lipid guidelines and avoid lifetime exposure to potentially damaging PRS-dependent LDL-C levels.

Response to Polygenic Risk: Results of the MyGeneRank Mobile Application-Based Coronary Artery Disease Study

“…PRSs for coronary artery disease (CAD) are of special interest given that CAD is a highly heritable condition and the leading cause of preventable death in the developed world (11)(12)(13)(14). While there remains some debate regarding the precise utility of CAD PRSs in risk stratification (15)(16)(17)(18), high polygenic risk has been independently and repeatedly associated with enhanced benefit from lipid lowering therapy (19)(20)(21)(22)(23)(24). This allows a CAD PRS to act as a "risk-enhancer" in any CAD preventive health-decision making scenario, beyond its contribution to risk stratification (14,25,26).…”