Summary
This Mendelian randomization study examined whether the cardiovascular benefit of lowering LDL-cholesterol depends on the biological mechanism by which it is lowered. Using genetic variants in CETP and HMGCR genes as instruments, the authors found that CETP variants—which raise HDL-C and lower LDL-C and apoB—were associated with reduced cardiovascular risk, whilst the magnitude of benefit per unit LDL-C reduction was similar to that observed with statin-related HMGCR variants. The findings suggest that the pathway through which LDL-C is lowered may influence clinical outcomes.
UK applicability
This UK-inclusive international study provides evidence relevant to cardiovascular risk assessment and lipid management strategies in UK primary and secondary care. The findings may inform understanding of why certain lipid-modifying therapies have differential clinical benefit beyond their effects on LDL-C levels.
Key measures
Odds ratios for major cardiovascular events; associations between CETP and HMGCR genetic scores and lipid levels (HDL-C, LDL-C, apolipoprotein B)
Outcomes reported
The study examined associations between genetic variants in CETP and HMGCR genes, changes in lipoprotein levels (HDL-C, LDL-C, apoB), and risk of major cardiovascular events using Mendelian randomization analyses across 102,837 participants in the primary analysis and 189,539 in validation cohorts.
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