Mendelian Randomization Study of ACLY and Cardiovascular Disease

ATP citrate lyase (ACLY) is an enzyme in the cholesterol biosynthesis pathway upstream of HMGCR, the target of statins. This study used Mendelian randomization to compare genetic variants mimicking ACLY inhibitors and statins (HMGCR inhibitors) in 654,783 participants. Both ACLY and HMGCR scores were associated with similar reductions in LDL cholesterol and comparable decreases in cardiovascular event risk per 10 mg/dL LDL reduction (odds ratios: 0.823 for ACLY, 0.836 for HMGCR). Neither variant increased cancer risk. The findings suggest ACLY inhibition lowers LDL cholesterol via the same mechanism as statins and may similarly reduce cardiovascular risk without adverse effects.

ATP citrate lyase (ACLY) is an enzyme in the cholesterol biosynthesis pathway upstream of HMGCR, the target of statins. This study used Mendelian randomization to compare genetic variants mimicking ACLY inhibitors and statins (HMGCR inhibitors) in 654,783 participants. Both ACLY and HMGCR scores were associated with similar reductions in LDL cholesterol and comparable decreases in cardiovascular event risk per 10 mg/dL LDL reduction (odds ratios: 0.823 for ACLY, 0.836 for HMGCR). Neither variant increased cancer risk. The findings suggest ACLY inhibition lowers LDL cholesterol via the same mechanism as statins and may similarly reduce cardiovascular risk without adverse effects.