PCSK9 genetic variants, carotid atherosclerosis and vascular remodelling

Background: Circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) is a crucial regulator of cholesterol metabolism. Loss-of-function variants in PCSK9 are associated with lower levels of circulating low-density lipoprotein cholesterol (LDL-C) and reduced cardiovascular disease (CVD) risk, while gain-of-function variants correlate with elevated LDL-C concentrations and increased CVD risk. This study investigated whether genetically determined LDL-C levels, proxied by four PCSK9 genetic variants, influence common carotid artery atherosclerosis. Methods: The analysis included 3040 European participants (mean age 64.2±5.4 years; 45.8% men) at high cardiovascular risk from the IMPROVE Study, alongside 49 088 individuals of white British ancestry (mean age 55.2±7.6 years; 47.9% men) from the UK Biobank (UKB). Ultrasonographic measurements of common carotid intima-media thickness (CC-IMTmean, CC-IMTmax, CC-IMTmean-max) were obtained. Four lipid-level affecting genetic variants in the PCSK9 locus were selected for analysis, both individually and in a standardised Lipid-Lowering Allelic Score (LLAS), to assess their effects on LDL-C and PCSK9 levels in the IMPROVE cohort and on ultrasonographic measures in both IMPROVE and UKB. Results: In the IMPROVE cohort, PCSK9 variants (rs11206510, rs2479409, rs11591147, rs11583680) exhibited expected effect directions, although not all statistically significant, on LDL-C and PCSK9 levels. The LLAS was negatively correlated with CC-IMTmean, CC-IMTmax and CC-IMTmean-max among women in IMPROVE, and among men and overall in UKB (all p<0.05). Effect sizes were comparable between cohorts. Conclusions: Genetic variants in the PCSK9 locus influence LDL-C levels and CC-IMT, in keeping with proven benefits of PCSK9 inhibitors on atherosclerotic cardiovascular events.