Functional Characterization of LIPA (Lysosomal Acid Lipase) Variants Associated with Coronary Artery Disease

Trent D. Evans, Xiangyu Zhang, Reece E. Clark, Arturo Alisio, Eric Song, Hanrui Zhang, Muredach P. Reilly, Nathan O. Stitziel, Babak Razani

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Objective: LIPA (lysosomal acid lipase) mediates cholesteryl ester hydrolysis, and patients with rare loss-of-function mutations develop hypercholesterolemia and severe disease. Genome-wide association studies of coronary artery disease have identified several tightly linked, common intronic risk variants in LIPA which unexpectedly associate with increased mRNA expression. However, an exonic variant (rs1051338 resulting in T16P) in linkage with intronic variants lies in the signal peptide region and putatively disrupts trafficking. We sought to functionally investigate the net impact of this locus on LIPA and whether rs1051338 could disrupt LIPA processing and function to explain coronary artery disease risk. Approach and Results: In monocytes isolated from a large cohort of healthy individuals, we demonstrate both exonic and intronic risk variants are associated with increased LIPA enzyme activity coincident with the increased transcript levels. To functionally isolate the impact of rs1051338, we studied several in vitro overexpression systems and consistently observed no differences in LIPA expression, processing, activity, or secretion. Further, we characterized a second common exonic coding variant (rs1051339), which is predicted to alter LIPA signal peptide cleavage similarly to rs1051338, yet is not linked to intronic variants. rs1051339 also does not impact LIPA function in vitro and confers no coronary artery disease risk. Conclusions: Our findings show that common LIPA exonic variants in the signal peptide are of minimal functional significance and suggest coronary artery disease risk is instead associated with increased LIPA function linked to intronic variants. Understanding the mechanisms and cell-specific contexts of LIPA function in the plaque is necessary to understand its association with cardiovascular risk.

Original languageEnglish
Pages (from-to)2480-2491
Number of pages12
JournalArteriosclerosis, thrombosis, and vascular biology
Volume39
Issue number12
DOIs
StatePublished - Dec 1 2019

Keywords

  • atherosclerosis
  • coronary artery disease
  • human genetics
  • monocytes
  • risk

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