A Genome-Wide Association Study Identifies LIPA as a Susceptibility Gene for Coronary Artery Disease

Abstract

Background eQTL analyses are important to improve the understanding of genetic association results. Here, we performed a genome-wide association and global gene expression study to identify functionally relevant variants affecting the risk of coronary artery disease (CAD). Methods and Results In a genome-wide association analysis of 2,078 CAD cases and 2,953 controls, we identified 950 single nucleotide polymorphisms (SNPs) that were associated with CAD at P<10-3. Subsequent in silico and wet-lab replication stages and a final meta-analysis of 21,428 CAD cases and 38,361 controls revealed a novel association signal at chromosome 10q23.31 within the LIPA (Lysosomal Acid Lipase A) gene (P=3.7×10-8; OR 1.1; 95% CI: 1.07-1.14). The association of this locus with global gene expression was assessed by genome-wide expression analyses in the monocyte transcriptome of 1,494 individuals. The results showed a strong association of this locus with expression of the LIPA transcript (P=1.3×10-96). An assessment of LIPA SNPs and transcript with cardiovascular phenotypes revealed an association of LIPA transcript levels with impaired endothelial function (P=4.4×10-3). Conclusions The use of data on genetic variants and the addition of data on global monocytic gene expression led to the identification of the novel functional CAD susceptibility locus LIPA, located on chromosome 10q23.31. The respective eSNPs associated with CAD strongly affect LIPA gene expression level, which itself was related to endothelial dysfunction, a precursor of CAD.

Regulation of Lipid Droplet Cholesterol Efflux From Macrophage Foam Cells

“…49,50 On the other hand, 2 recent genome-wide association studies report links of a gain-of-function LAL mutation with enhanced susceptibility to coronary artery disease. 51,52 Elevated LAL expression, presumably leading to increased LAL activity, was associated with lower high-density lipoprotein cholesterol levels. 52 Follow-up functional studies are required to clarify how either low or high LAL activity is protective or causative of premature coronary artery disease and to further evaluate how macrophage-specific LAL activity influences atherosclerotic lesions, but it is clear that LAL plays an important role in the pathogenesis of atherosclerosis and coronary artery disease.…”

Intact endothelial autophagy is required to maintain vascular lipid homeostasis

“…Given that chloroquine works as an inhibitor of lysosomal processes, the most likely explanation is that similar to what has been described in other tissues; endothelial cells rely, at least in part, on autophagosomal-mediated delivery of lipids to the lysosome for degradation. In this context, it may be relevant that the gene lysosomal acid lipase A (LIPA) has been recently identified in genome-wide studies as a potential susceptibility locus for atherosclerotic disease (Wild et al, 2011;Vargas-Alarcon et al, 2013). In addition, it is of potential interest that a number of genes associated with lipid metabolism have also been linked to age-related retinal diseases (Black & Clark, 2015).…”

Genomewide Association Studies in Cardiovascular Disease—An Update 2011

“…They subsequently analyzed the effect on gene expression for each CAD-associated SNP (33 ). This approach revealed a novel CAD-susceptibility locus on chromosome 10q23.31, with the lead SNPs, rs1412444 and rs2246833, located in intronic regions of the LIPA (lipase A, lysosomal acid, cholesterol esterase) gene, which encodes lysosomal acid lipase A.…”

“…Furthermore, GWAS results mostly have a minimal to modest impact on risk stratification, diagnosis, and genetic prevention and treatment at the individual level. Consequently, a substantial gap exists in our understanding of how genetic variants affect the pathophysiological mechanisms through which these susceptibility loci contribute to disease (33 ). Hence, the next challenge is to link association signals with biological function, and extensive additional genetic and molecular studies are needed to identify causative variants responsible for disease susceptibility.…”