A Polygenic Risk Score for Low-density Lipoprotein Cholesterol is Associated with Risk of Ischemic Heart Disease and Enriches for Individuals with Familial Hypercholesterolemia.
Circ Genom Precis Med. 2021 Jan 13;:
Authors: Wu H, Forgetta V, Zhou S, Bhatnagar SR, Paré G, Richards JB
Background – The clinical implications of a polygenic risk score (PRS) for low-density lipoprotein cholesterol (LDL-C) are not well understood, both within the general population and individuals with familial hypercholesterolemia (FH). Methods – We developed the LDL-C PRS using LASSO regression in 377,286 white British participants from UK Biobank and tested its association with LDL-C according to FH variant carrier status in another 41,748 whole-exome sequenced individuals. Next, we tested for an enrichment of FH variant carriers amongst individuals with severe hypercholesterolemia and low LDL-C PRS. Last, we contrasted the effect of the LDL-C PRS, measured LDL-C and FH variant carrier status on risk of ischemic heart disease (IHD) amongst 3,010 cases and 38,738 controls. Results – Amongst the 41,748 whole-exome sequenced white British individuals, one SD increase in the LDL-C PRS was associated with elevated LDL-C amongst both FH variant carriers (0.34, 95% CI 0.22 to 0.47 mmol/L) and non-carriers (0.42, 95% CI 0.42 to 0.43 mmol/L). Amongst individuals with severe hypercholesterolemia, FH variant carriers were enriched in those with a low LDL-C PRS (OR 2.20, 95% CI 1.66 to 2.71 per SD). Each SD increase in the LDL-C PRS was associated with risk of IHD to the comparable magnitude as measured LDL-C (OR 1.24, 95% CI 1.20 to 1.29 and OR 1.15, 95% CI 1.09 to 1.23, respectively). The LDL-C PRS was not strongly associated with other traditional IHD risk factors. Conclusions – An LDL-C PRS could be used to identify individuals with a higher probability of harboring FH variants. The association between IHD and the LDL-C PRS was comparable to measured LDL-C, likely because the PRS reflects lifetime exposure to LDL-C levels.
PMID: 33440130 [PubMed – as supplied by publisher]