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

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