The impact of partial and complete loss-of-function mutations in endothelial lipase on high-density lipoprotein levels and functionality in humans

Roshni R. Singaraja, Suthesh Sivapalaratnam, Kees Hovingh, Marie Pierre Dubé, José Castro-Perez, Heidi L. Collins, Steven J. Adelman, Meliana Riwanto, Jasmin Manz, Brian Hubbard, Ian Tietjen, Kenny Wong, Lyndon J. Mitnaul, Margaret Van Heek, Linus Lin, Thomas A. Roddy, Jason McEwen, Geesje Dallinge-Thie, Leonie Van Vark-Van Der Zee, Germaine VerwoertMichael Winther, Cornelia Van Duijn, Albert Hofman, Mieke D. Trip, A. David Marais, Bela Asztalos, Ulf Landmesser, Eric Sijbrands, John J. Kastelein, Michael R. Hayden

Research output: Contribution to journalReview articlepeer-review

56 Scopus citations

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. Methods and 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.

Original languageEnglish
Pages (from-to)54-62
Number of pages9
JournalCirculation: Cardiovascular Genetics
Volume6
Issue number1
DOIs
StatePublished - Feb 2013

Keywords

  • Cardiovascular disease
  • Genetics
  • High-density lipoprotein cholesterol
  • Lipids

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