title: Coronary Artery Disease-AssociatedLIPACoding Variant rs1051338 Reduces Lysosomal Acid Lipase Levels and Activity in Lysosomes.
abstract: Genome-wide association studies have linked variants at chromosome 10q23 with increased coronary artery disease risk. The disease-associated variants fall inLIPA, which encodes lysosomal acid lipase (LAL), the enzyme responsible for lysosomal cholesteryl ester hydrolysis. Loss-of-function mutations inLIPAresult in accelerated atherosclerosis. Surprisingly, the coronary artery disease variants are associated with increasedLIPAexpression in some cell types. In this study, we address this apparent contradiction.
  
  
  
  We investigated a coding variant rs1051338, which is in high linkage disequilibrium (r2=0.89) with the genome-wide association study lead-associated variant rs2246833 and causes a nonsynonymous threonine to proline change within the signal peptide of LAL. Transfection of allele-specific expression constructs showed that the risk allele results in reduced lysosomal LAL protein (P=0.004) and activity (P=0.005). Investigation of LAL localization and turnover showed the risk LAL protein is degraded more quickly. This mechanism was confirmed in disease-relevant macrophages from individuals homozygous for either the nonrisk or risk allele. There was no difference in LAL protein or activity in whole macrophage extracts; however, we found reduced LAL protein (P=0.02) and activity (P=0.026) with the risk genotype in lysosomal extracts, suggesting that the risk genotype affects lysosomal LAL activity. Inhibition of the proteasome resulted in equal amounts of lysosomal LAL protein in risk and nonrisk macrophages.
  
  
  
  Our findings show that the coronary artery disease-associated coding variant rs1051338 causes reduced lysosomal LAL protein and activity because of increased LAL degradation, providing a plausible causal mechanism of increased coronary artery disease risk.
authors.affiliation: From the Department of Cardiovascular Sciences, University of Leicester and National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, United Kingdom.
authors.forename: Gavin E
authors.initials: GE
authors.lastname: Morris
authors.affiliation: From the Department of Cardiovascular Sciences, University of Leicester and National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, United Kingdom.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Braund
authors.affiliation: From the Department of Cardiovascular Sciences, University of Leicester and National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, United Kingdom.
authors.forename: Jasbir S
authors.initials: JS
authors.lastname: Moore
authors.affiliation: From the Department of Cardiovascular Sciences, University of Leicester and National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, United Kingdom.
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.affiliation: From the Department of Cardiovascular Sciences, University of Leicester and National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, United Kingdom.
authors.forename: Veryan
authors.initials: V
authors.lastname: Codd
authors.affiliation: From the Department of Cardiovascular Sciences, University of Leicester and National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, United Kingdom. tw126@le.ac.uk.
authors.forename: Tom R
authors.initials: TR
authors.lastname: Webb
mesh_terms: D000328:Adult; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003324:Coronary Artery Disease / Q000201:enzymology* / Q000235:genetics*; D015536:Down-Regulation; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006720:Homozygote; D006801:Humans; D015810:Linkage Disequilibrium; D008247:Lysosomes / Q000187:drug effects / Q000201:enzymology*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology; D021382:Protein Sorting Signals; D021381:Protein Transport; D059748:Proteolysis; D012307:Risk Factors; D002787:Sterol Esterase / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection
chemical_list: D061988:Proteasome Inhibitors; D021382:Protein Sorting Signals; C503451:LIPA protein, human; D002787:Sterol Esterase; D046988:Proteasome Endopeptidase Complex
keywords: coronary artery disease; genome-wide association study; lipase; macrophage