Summary
This Mendelian randomisation study examined whether the cardiovascular benefit of lowering LDL-cholesterol depends on the biological pathway through which it is lowered. Using genetic variants in CETP and HMGCR genes as natural experiments, the authors found that CETP variants—which raise HDL-C and lower LDL-C—were associated with reduced cardiovascular risk comparable to statin-induced LDL-C lowering, suggesting that different mechanisms of lipoprotein modification may have similar clinical benefits.
UK applicability
The findings are relevant to UK clinical practice and lipid management guidelines, as they provide mechanistic evidence about how different pharmacological approaches to lipid modification (CETP inhibitors versus statins) relate to cardiovascular outcomes. However, the study population was primarily North American or UK-based historical cohorts, so direct applicability to contemporary UK populations requires consideration of secular trends in cardiovascular risk factors.
Key measures
CETP and HMGCR genetic scores; high-density lipoprotein cholesterol (HDL-C); low-density lipoprotein cholesterol (LDL-C); apolipoprotein B (apoB); odds ratio (OR) for major cardiovascular events
Outcomes reported
The study measured associations between genetic variants in CETP and HMGCR genes, lipid/lipoprotein levels (HDL-C, LDL-C, apoB), and major cardiovascular events in a large multi-cohort population. External validation assessed coronary heart disease risk in an independent participant cohort.
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