title: The impact of partial and complete loss-of-function mutations in endothelial lipase on high-density lipoprotein levels and functionality in humans.
abstract: BACKGROUND
  Endothelial lipase is a phospholipase with activity against high-density lipoprotein. Although a small number of mutations in LIPG have been described, the role of LIPG in protection against atherosclerosis is unclear.
  
  
  RESULTS
  We identified 8 loss-of-function (LOF) mutations in LIPG in individuals with high-density lipoprotein cholesterol. Functional analysis confirmed that most rare mutations abolish lipase activity in vitro, indicating complete LOF, whereas 2 more common mutations N396S and R476W reduce activity by ≈50%, indicating partial LOF and implying ≈50% and ≈75% remaining endothelial lipase function in heterozygous complete LOF and partial LOF mutation carriers, respectively. complete LOF mutation carriers had significantly higher plasma high-density lipoprotein cholesterol levels compared with partial LOF mutation carriers. Apolipoprotein B-depleted serum from complete LOF carriers showed significantly enhanced cholesterol efflux acceptor capacity, whereas only trends were observed in partial LOF carriers. Carriers of LIPG mutations exhibited trends toward reduced coronary artery disease in 4 independent cohorts (meta-analysis odds ratio, 0.7; P=0.04).
  
  
  CONCLUSIONS
  Our data suggest that the impact of LIPG mutations is directly related to their effect on endothelial lipase function and support that antagonism of endothelial lipase function improves cardioprotection.
authors.affiliation: Xenon Pharmaceuticals Inc., Burnaby, Canada.
authors.forename: Roshni R
authors.initials: RR
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authors.forename: Suthesh
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authors.lastname: Dubé
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authors.forename: Heidi L
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authors.forename: Lyndon J
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authors.lastname: Mitnaul
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authors.lastname: van Heek
authors.forename: Linus
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authors.lastname: Lin
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Roddy
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authors.forename: Geesje
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authors.lastname: Dallinge-Thie
authors.forename: Leonie
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authors.lastname: van Vark-van der Zee
authors.forename: Germaine
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authors.lastname: Verwoert
authors.forename: Michael
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authors.lastname: Winther
authors.forename: Cornelia
authors.initials: C
authors.lastname: van Duijn
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Mieke D
authors.initials: MD
authors.lastname: Trip
authors.forename: A David
authors.initials: AD
authors.lastname: Marais
authors.forename: Bela
authors.initials: B
authors.lastname: Asztalos
authors.forename: Ulf
authors.initials: U
authors.lastname: Landmesser
authors.forename: Eric
authors.initials: E
authors.lastname: Sijbrands
authors.forename: John J
authors.initials: JJ
authors.lastname: Kastelein
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
mesh_terms: D008076:Cholesterol, HDL / Q000097:blood*; D015331:Cohort Studies; D003324:Coronary Artery Disease / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D008049:Lipase / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense
chemical_list: D008076:Cholesterol, HDL; C410382:LIPG protein, human; D008049:Lipase