PCSK9 genetic variants, carotid atherosclerosis and vascular remodelling

Background and aimsCirculating 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. MethodsThe analysis included 3,040 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 standardized polygenic risk score (PRS), to assess their effects on LDL-C and PCSK9 levels in the IMPROVE cohort and on ultrasonographic measures in both IMPROVE and UKB. ResultsIn the IMPROVE cohort, PCSK9 variants (rs11206510, rs2479409, rs11591147, rs11583680) exhibited expected effect directions, albeit not all statistically significant, on LDL-C and PCSK9 levels. The PRS 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. ConclusionsGenetic variants in the PCSK9 locus influence LDL-C levels and CC-IMT, in keeping with proven benefits of PCSK9 inhibitors on atherosclerotic cardiovascular events.