Benoit J. Arsenault

Background: Lp(a) (lipoprotein[a]) is a highly atherogenic lipoprotein subfraction that may contribute to polygenic risk of coronary artery disease (CAD), but the extent of this contribution is unknown. Our objective was to estimate the contribution of Lp(a) to polygenic risk of CAD and to evaluate the respective contributions of Lp(a) and a CAD polygenic risk score (PRS) to CAD. Methods: A total of 372 385 UK Biobank participants of European ancestry free of CAD at baseline were included. Plasma Lp(a) levels were measured and a CAD-PRS was calculated using the LDpred2 algorithm. Over the median follow-up of 12.6 years, 13 538 participants had incident CAD (myocardial infarction, coronary artery bypass grafting, or coronary angioplasty). Results: The LPA region contribution to the CAD-PRS-mediated CAD risk was modest (7.2% [95% CI, 6.1–8.3]). Lp(a) levels significantly increased the predictive performance of a CAD-PRS including age and sex in Cox regression (C statistic 0.751 versus 0.746, difference, 0.005 [95% CI, 0.004–0.006]). Compared with participants in the bottom CAD-PRS quintile with Lp(a) levels <25 nmol/L (CAD event rate, 1.4%), the hazard ratio for incident CAD in participants in the top CAD-PRS quintile with Lp(a) levels ≥125 nmol/L was 5.45 (95% CI, 4.93–6.03; P =9.35×10 -242 , CAD event rate 6.6%). Conclusions: Compared with individuals with a low genetic risk of CAD (low CAD-PRS and low Lp[a] levels), those with a high genetic risk (high CAD-PRS and high Lp[a] levels) had a 5-fold higher CAD risk. These results highlight a substantial contribution of genetic risk factors to CAD and that accurate estimation of genetic risk of CAD may need to consider blood levels of Lp(a).