Abstract 165: Functional Consequences of a Lysosomal Acid Lipase Variant Associated With Coronary Artery Disease

• DOI: 10.1161/atvb.37.suppl_1.165
• Publication Date: 2021-07-02T23:44:11Z
• Authors: Trent D Evans; Reece Clark; In-Hyuk Jung; Arturo Alisio; Nathan O Stitziel; Babak Razani
• Keywords: Coding region; SNP

Two tightly linked common intronic variants at the LIPA locus (which encodes for Lysosomal Acid Lipase - LAL) are present in nearly one-third of population and known to increase risk coronary artery disease (CAD) by 13-17% large-scale genome-wide association studies. LAL mediates hydrolysis cholesteryl esters patients with rare loss-of-function mutations develop hypercholesterolemia CAD. However, these non-coding, not associated lipid abnormalities, result increased transcripts monocytes, a constellation findings that has hindered further mechanistic understanding. We have discovered previously unrecognized coding variant tight linkage is equally CAD risk. This involves shift from nonpolar polar amino acid (T16P) predicted signal peptide region LAL, providing highly biologically plausible link altered enzyme trafficking function. hypothesized causative SNP altering subcellular distribution activity functional consequences handling. In monocytes isolated large cohort human patients, we show leads both mRNA expression whole-cell lysates. To more precisely implicate variant’s effects on function, studied several vitro overexpression models assessing absence variants. T16P alteration sufficient alter away lysosome portion favoring secretory pathway. These important implications macrophage handling atherosclerotic plaque provide novel mechanism one most genomic cardiovascular disease.