Mendelian Randomization Study of ACLY and Cardiovascular Disease

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.).

Figure 1. Associations of the ACLY and HMGCR Scores with Changes in the Concentration and Lipid Composition of Plasma Lipoproteins.

HMGCR (3-hydroxy-3-methylglutaryl–coenzyme A reductase) scores are shown in blue, and ACLY (ATP citrate lyase) scores are shown in red. Data are from analyses involving 65,976 participants for whom lipid traits measured with the use of nuclear magnetic resonance spectroscopy were available. The change for each lipid trait is expressed as a percentage of the change in the low-density lipoprotein (LDL) cholesterol level, with both measurements in SD units. Boxes represent point estimates of effect, and lines 95% confidence intervals. HDL denotes high-density lipoprotein, IDL intermediate-density lipoprotein, and VLDL very-low-density lipoprotein.

Figure 2. Associations of the Genetic Scores with the Risk of Cardiovascular Events.

Panel A shows the association between the ACLY score and the risk of cardiovascular events per decrease of 10 mg per deciliter in the LDL cholesterol level, and Panel B shows the comparison of the association of the ACLY score and that of the other genetic scores with the risk of major cardiovascular events for the same decrease of 10 mg per deciliter in the LDL cholesterol level. Data on major cardiovascular events and myocardial infarctions are from analyses involving the total study sample of 654,783 participants; these analyses included both individual participant–level and summary-level data. Data on major coronary events, coronary heart disease, coronary revascularization, and death from coronary heart disease are from the sample of 470,478 participants for whom individual-level data on these outcomes were available. Associations for all genetic scores are given for a standardized decrement of 10 mg per deciliter in the LDL cholesterol level. Boxes represent point estimates of effect, and lines 95% confidence intervals. Major coronary events were defined as the composite of nonfatal myocardial infarction, coronary revascularization, or death from coronary heart disease. Coronary heart disease was defined as the composite of nonfatal myocardial infarction or death from coronary heart disease, and coronary revascularization was defined as percutaneous coronary intervention or coronary-artery bypass grafting surgery. LDLR denotes LDL receptor, NPC1L1 Niemann–Pick C1–like 1, and PCSK9 proprotein convertase subtilisin–kexin type 9.

Figure 3. Associations of the ACLY Score, Alone and in Combination with the HMGCR and NPC1L1 Scores, with Lipoprotein Levels and the Risk of Major Cardiovascular Events.

Panel A shows the stratified analysis. Panel B shows a two-by-two (2×2) factorial mendelian randomization analysis of ACLY and HMGCR scores. Panel C shows a two-by-two factorial mendelian randomization analysis of ACLY and NPC1L1 scores. Data are from analyses involving 470,478 participants for whom individual participant data, including 44,628 cases of major cardiovascular events, were available. Changes in lipid levels were obtained from 72,411 participants with individual participant data who were enrolled in the Database of Genotypes and Phenotypes (dbGAP) or the U.K. National Health Service Blood and Transplant INTERVAL study and for whom one or more lipid measurements were available. The solid boxes represent point estimates of effect, and lines 95% confidence intervals.