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 Nicholls

Research output: Contribution to journalArticle

12 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.

LanguageEnglish
Pages1033-1042
Number of pages10
JournalNew England Journal of Medicine
Volume380
Issue number11
DOIs
Publication statusPublished - 14 Mar 2019

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Ference, B. A., Ray, K. K., Catapano, A. L., Ference, T. B., Burgess, S., Neff, D. R., ... Nicholls, S. (2019). Mendelian randomization study of ACLY and cardiovascular disease. New England Journal of Medicine, 380(11), 1033-1042. https://doi.org/10.1056/NEJMoa1806747
Ference, Brian A. ; Ray, Kausik K. ; Catapano, Alberico L. ; Ference, Thatcher B. ; Burgess, Stephen ; Neff, David R. ; Oliver-Williams, Clare ; Wood, Angela M. ; Butterworth, Adam S. ; Di Angelantonio, Emanuele ; Danesh, John ; Kastelein, John J.P. ; Nicholls, Stephen. / Mendelian randomization study of ACLY and cardiovascular disease. In: New England Journal of Medicine. 2019 ; Vol. 380, No. 11. pp. 1033-1042.
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title = "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.",
author = "Ference, {Brian A.} and Ray, {Kausik K.} and Catapano, {Alberico L.} and Ference, {Thatcher B.} and Stephen Burgess and Neff, {David R.} and Clare Oliver-Williams and Wood, {Angela M.} and Butterworth, {Adam S.} and {Di Angelantonio}, Emanuele and John Danesh and Kastelein, {John J.P.} and Stephen Nicholls",
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Ference, BA, Ray, KK, Catapano, AL, Ference, TB, Burgess, S, Neff, DR, Oliver-Williams, C, Wood, AM, Butterworth, AS, Di Angelantonio, E, Danesh, J, Kastelein, JJP & Nicholls, S 2019, 'Mendelian randomization study of ACLY and cardiovascular disease', New England Journal of Medicine, vol. 380, no. 11, pp. 1033-1042. https://doi.org/10.1056/NEJMoa1806747

Mendelian randomization study of ACLY and cardiovascular disease. / Ference, Brian A.; Ray, Kausik K.; Catapano, Alberico L.; Ference, Thatcher B.; Burgess, Stephen; Neff, David R.; Oliver-Williams, Clare; Wood, Angela M.; Butterworth, Adam S.; Di Angelantonio, Emanuele; Danesh, John; Kastelein, John J.P.; Nicholls, Stephen.

In: New England Journal of Medicine, Vol. 380, No. 11, 14.03.2019, p. 1033-1042.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Mendelian randomization study of ACLY and cardiovascular disease

AU - Ference, Brian A.

AU - Ray, Kausik K.

AU - Catapano, Alberico L.

AU - Ference, Thatcher B.

AU - Burgess, Stephen

AU - Neff, David R.

AU - Oliver-Williams, Clare

AU - Wood, Angela M.

AU - Butterworth, Adam S.

AU - Di Angelantonio, Emanuele

AU - Danesh, John

AU - Kastelein, John J.P.

AU - Nicholls, Stephen

PY - 2019/3/14

Y1 - 2019/3/14

N2 - 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.

AB - 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.

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U2 - 10.1056/NEJMoa1806747

DO - 10.1056/NEJMoa1806747

M3 - Article

VL - 380

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JO - New England Journal of Medicine

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Ference BA, Ray KK, Catapano AL, Ference TB, Burgess S, Neff DR et al. Mendelian randomization study of ACLY and cardiovascular disease. New England Journal of Medicine. 2019 Mar 14;380(11):1033-1042. https://doi.org/10.1056/NEJMoa1806747