ATP-citrate lyase and chronic kidney disease
ATP-citrate lyase (ACLY) inhibition is a therapeutic strategy under investigation for atherosclerotic cardiovascular disease, non-alcoholic steatohepatitis, and metabolic syndrome. Mouse models suggest ACLY inhibition could reduce inflammation and kidney fibrosis.

Researchers constructed a genetic instrument by selecting variants associated with ACLY expression in the expression quantitative trait loci genetics consortium (eQTLGen) from blood samples from 31,684 participants. In a two-sample Mendelian randomization analysis, we evaluated the effect of genetically predicted ACLY expression on the risk of CKD, estimated glomerular filtration rate (eGFR), and albumin-to-creatinine ratio (ACR) using the CKD Genetics consortium (CKDGen), United Kingdom biobank, and the Finnish Genetics consortium (FinnGen) totaling 66,396 CKD cases and 958,517 controls.

ACLY is constitutively expressed in all cell types including in whole blood. The genetic instrument included 13 variants and explained 1.5% of the variation in whole blood ACLY gene expression. A 34% reduction in ACLY expression score was associated with a 0.04 mmol/L reduced low-density lipoprotein cholesterol (P = 3.4 x 10-4) and a 9% reduced risk of CKD (stage 3,4,5, dialysis or eGFR below 60 ml/min/1.73m2) (odds ratio = 0.91, 95% C.I. 0.85-0.98, P = 0.008), but no association was observed with either eGFR or ACR. Mendelian randomization analyses showed genetically reduced ACLY expression was associated with reduced risk of CKD but had no effect on either eGFR or ACR.