Summary
This Mendelian randomisation study examined whether the cardiovascular benefit of lowering LDL-cholesterol depends on the mechanism of reduction, comparing genetic variants affecting CETP (which raises HDL-C and lowers LDL-C) and HMGCR (the statin target). Across 102,837 participants with 13,821 cardiovascular events, CETP-associated variants were linked to lower cardiovascular risk despite LDL-C reduction, and showed similar magnitude of protection per unit LDL-C change as HMGCR variants, suggesting the pathway of cholesterol modification may influence clinical outcomes.
UK applicability
These findings are directly relevant to UK cardiovascular prevention policy and statin prescribing guidelines, as they inform understanding of how different lipid-lowering mechanisms affect disease risk. The study population included UK participants and the results have implications for risk stratification and lipid management strategies in the NHS.
Key measures
Odds ratios for major cardiovascular events; mean differences in HDL-C, LDL-C, and apolipoprotein B levels; CETP and HMGCR genetic scores
Outcomes reported
The study measured associations between genetic variants in CETP and HMGCR genes, lipid/lipoprotein levels (HDL-C, LDL-C, apoB), and risk of major cardiovascular events using Mendelian randomisation analyses. Findings were validated across multiple large cohorts and case-control studies.
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