Mendelian randomization study of ACLY and cardiovascular disease

Brian A. Ference, Kausik K. Ray, Alberico L. Catapano, Thatcher B. Ference, Stephen Burgess, David R. Neff, Clare Oliver-Williams, Angela M. Wood, Adam S. Butterworth, Emanuele Di Angelantonio, John Danesh, John J.P. Kastelein, Stephen J. Nicholls

Research output: Contribution to journalArticlepeer-review

236 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1033-1042
Number of pages10
JournalNew England Journal of Medicine
Volume380
Issue number11
DOIs
Publication statusPublished or Issued - 14 Mar 2019
Externally publishedYes

ASJC Scopus subject areas

  • General Medicine

Cite this