Mendelian Randomization Study of ACLY and Cardiovascular Disease

Mendelian Randomization Study of ACLY and Cardiovascular DiseaseTo the Editor: Ference et al. (March 14, 2019, issue) 1 tested the association of plasma low-density lipoprotein (LDL) cholesterol and cardiovascular disease with genetic variants in a 1-millionbase span around the gene encoding ATP citrate lyase (ACLY) and concluded that human genetics validates ACLY as a therapeutic target for cardiovascular disease.Compelling support for this assertion requires that the utilized genetic variants capture inborn variability in the activity of ACLY. 2 However, none of the variants were shown by Ference et al. to affect the quantity or quality of the ACLY gene product.Support for the authors' assertion also requires that the genetic variants reproducibly associate with the exposure (LDL cholesterol). 3Among 99,154 participants in the Veterans Affairs Million Veteran Program, 4 we found that only one of the nine variants was associated with LDL cholesterol levels (see the figure in the Supplementary Appendix, available with the full text of this letter at NEJM.org).Given that the other genetic variants were not associated with LDL cholesterol levels, it is not surprising that we found no association of an aggregate score of these nine variants with coronary heart disease in an independent set of 87,644 case patients with coronary heart disease and 94,463 controls without such disease.This null result for ACLY is in stark contrast to the score of seven variants at the gene encoding proprotein convertase subtilisin-kexin type 9 (PCSK9) reported by Ference et al.Our human genetics findings do not add support to ACLY as a therapeutic target for cardiovascular disease.