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Mendelian Randomization Study of ACLY and Cardiovascular Disease.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Ference, Brian A 
Ray, Kausik K 
Catapano, Alberico L 
Ference, Thatcher B 

Abstract

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.).

Description

Keywords

ATP Citrate (pro-S)-Lyase, Cardiovascular Diseases, Cholesterol, LDL, Diabetes Mellitus, Dicarboxylic Acids, Fatty Acids, Female, Genetic Predisposition to Disease, Humans, Hydroxymethylglutaryl CoA Reductases, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypercholesterolemia, Hypolipidemic Agents, Lipoproteins, Male, Membrane Proteins, Membrane Transport Proteins, Mendelian Randomization Analysis, Middle Aged, Neoplasms, Odds Ratio, Risk, Triglycerides

Journal Title

N Engl J Med

Conference Name

Journal ISSN

0028-4793
1533-4406

Volume Title

380

Publisher

Massachusetts Medical Society
Sponsorship
Medical Research Council (MR/S003746/1)
British Heart Foundation (None)
Medical Research Council (MC_UU_00002/7)
British Heart Foundation (RG/18/13/33946)
Wellcome Trust (204623/Z/16/Z)
Medical Research Council (MR/L003120/1)
This study was funded in part by an investigator-initiated grant from Esperion Therapeutics, Inc. The sponsor had no access to the data; had no role in the design, conduct or analysis of the study; had no role in the drafting of the manuscript or its content; and did not participate in the decision to submit for publication.