Related Experiment Video
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.).
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.
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