LIPA Variants in Genome-Wide Association Studies of Coronary Artery Diseases: Loss-of-Function or Gain-of-Function?

Genome-wide association studies (GWASs) have identified multiple coronary artery disease (CAD) risk loci, yet moving from association to mechanistic insights and therapeutic translation remains a major challenge. Several GWASs have identified LIPA as a novel locus for CAD. LIPA encodes lysosomal acid lipase (LAL), the major lysosomal enzyme hydrolyzing cholesteryl esters (CEs) and triglycerides derived from lipoproteins taken up by cells. Before its GWAS discovery for CAD, loss-of-function (LOF) mutations in LIPA were identified as the cause of rare Mendelian disorders, including Wolman disease, an infantile-onset disorder due to complete LOF mutations, as well as cholesteryl ester storage disease (CESD), a later-onset disorder with residual LAL activity resulting in hepatosplenomegaly, hyperlipidemia, liver failure, and premature atherosclerosis. Although rare LIPA LOF alleles in CESD are linked to accelerated atherosclerosis and hyperlipidemia, surprisingly the common LIPA CAD risk alleles are not associated with altered plasma lipids, liver traits, or reduced expression of LIPA in liver. Indeed, the CAD risk alleles have no expression quantitative trait locus (eQTL) in liver tissue yet do, however, have eQTLs for higher LIPA mRNA in monocytes and macrophages.