Genetic and measured LDL-C: Differential and interactive effects on cardiovascular and stroke subtypes

Abstract

Background: Low-density lipoprotein cholesterol (LDL-C), a key contributor to coronary artery disease (CAD), increases mortality. While lowering LDL-C is protective, concerns remain that very low levels may increase hemorrhagic stroke risk. This study explored genetic and environmental determinants of LDL-C to understand these relationships. Methods: This analysis was conducted using the Korean Cancer Prevention Study-II (KCPS-II) with over 150 thousand participants. Using the microarray results from the KCPS-II biobank, a genome-wide association study (GWAS) was performed to identify genetic variations associated with LDL-C. Environmentally determined LDL-C (ELDL-C) was calculated by subtracting genetically determined LDL-C (GLDL-C) from the measured LDL-C (MLDL-C). MLDL-C, GLDL-C, and ELDL-C levels were divided into quintiles, and their associations with cardiovascular diseases were analyzed. BBJ-GWAS summary statistics were used for external validation. Results: In the final analysis of 136,263 participants, MLDL-C levels were associated with confounding factors, while GLDL-C was independent of these factors. GLDL-C demonstrated a linear association with ASCVD and IHD risk but no increased risk at lower levels for HS. Additionally, the lowest GLDL-C group did not show elevated HS risk in either the KCPS-II or BBJ-based analysis. Notably, even in high genetic risk groups, the risk of cardiovascular disease was reduced when environmentally determined ELDL-C was low. Conclusion: This study demonstrates that lower LDL-C levels are linearly associated with a reduced atherosclerotic cardiovascular disease risk. Furthermore, low LDL-C was not a risk factor for hemorrhagic stroke. These findings suggest that individuals with genetically high LDL-C can lower their cardiovascular risk through lifestyle modifications.