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Updated: Jan 10, 2026
Disorders of Erythrocytes
Mendelian Randomization Study of ACLY and Cardiovascular Disease
Brian A Ference1, Kausik K Ray1, Alberico L Catapano1
1From the Centre for Naturally Randomized Trials (B.A.F., T.B.F.), Medical Research Council, British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care (B.A.F., S.B., C.O.-W., A.M.W., A.S.B., E.D.A., J.D.), Medical Research Council Biostatistics Unit (S.B.), and NIHR Blood and Transplant Research Unit in Donor Health and Genomics (A.S.B., E.D.A., J.D.), University of Cambridge, Cambridge, and Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, School of Public Health, Imperial College London, London (K.K.R.) - all in the United Kingdom; the Department of Pharmacologic and Biomolecular Sciences, University of Milan and Multimedica IRCCS, Milan (A.L.C.); Michigan State University, East Lansing (D.R.N.); the Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam (J.J.P.K.); and Monash University, Clayton, VIC, Australia (S.J.N.).
Insights
Genetic inhibition of ATP citrate lyase (ACLY) and HMGCR lowers LDL cholesterol similarly, with comparable cardiovascular event risk reduction. Lifelong inhibition of either enzyme did not increase cancer risk.
Area of Science:
- Biochemistry
- Genetics
- Cardiovascular Medicine
Background:
- ATP citrate lyase (ACLY) is a cholesterol biosynthesis enzyme upstream of HMGCR, the target of statins.
- The safety and efficacy of genetic ACLY inhibition compared to HMGCR inhibition remain unclear.
Purpose of the Study:
- To compare the effects of genetic inhibition of ACLY and HMGCR on lipid levels, cardiovascular events, and cancer risk.
- To determine if ACLY inhibition offers similar cardiovascular benefits per unit LDL cholesterol reduction as statins.
Main Methods:
- Constructed genetic scores for ACLY and HMGCR using independently inherited variants.
- Analyzed associations of these genetic scores with plasma lipids, lipoproteins, and risks of cardiovascular events and cancer in a large cohort.
Main Results:
- Both ACLY and HMGCR genetic scores showed similar effects on lipid profiles and cardiovascular event risk reduction per LDL cholesterol decrease.
- Neither lifelong genetic ACLY nor HMGCR inhibition was associated with an increased risk of cancer.
Conclusions:
- Genetic variants mimicking ACLY inhibitors and statins lower LDL cholesterol via similar mechanisms.
- ACLY inhibition demonstrates comparable cardiovascular risk reduction to HMGCR inhibition per unit LDL reduction, without increasing cancer risk.
Background:
ATP citrate lyase is an enzyme in the cholesterol-biosynthesis pathway upstream of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the target of statins. Whether the genetic inhibition of ATP citrate lyase is associated with deleterious outcomes and whether it has the same effect, per unit decrease in the low-density lipoprotein (LDL) cholesterol level, as the genetic inhibition of HMGCR is unclear.
Methods:
We constructed genetic scores composed of independently inherited variants in the genes encoding ATP citrate lyase (ACLY) and HMGCR to create instruments that mimic the effect of ATP citrate lyase inhibitors and HMGCR inhibitors (statins), respectively. We then compared the associations of these genetic scores with plasma lipid levels, lipoprotein levels, and the risk of cardiovascular events and cancer.
Results:
A total of 654,783 participants, including 105,429 participants who had major cardiovascular events, were included in the study. The ACLY and HMGCR scores were associated with similar patterns of changes in plasma lipid and lipoprotein levels and with similar effects on the risk of cardiovascular events per decrease of 10 mg per deciliter in the LDL cholesterol level: odds ratio for cardiovascular events, 0.823 (95% confidence interval [CI], 0.78 to 0.87; P = 4.0×10-14) for the ACLY score and 0.836 (95% CI, 0.81 to 0.87; P = 3.9×10-19) for the HMGCR score. Neither lifelong genetic inhibition of ATP citrate lyase nor lifelong genetic inhibition of HMGCR was associated with an increased risk of cancer.
Conclusions:
Genetic variants that mimic the effect of ATP citrate lyase inhibitors and statins appeared to lower plasma LDL cholesterol levels by the same mechanism of action and were associated with similar effects on the risk of cardiovascular disease per unit decrease in the LDL cholesterol level. (Funded by Esperion Therapeutics and others.).
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