TY - JOUR
T1 - The impact of partial and complete loss-of-function mutations in endothelial lipase on high-density lipoprotein levels and functionality in humans
AU - Singaraja, Roshni R.
AU - Sivapalaratnam, Suthesh
AU - Hovingh, Kees
AU - Dubé, Marie Pierre
AU - Castro-Perez, José
AU - Collins, Heidi L.
AU - Adelman, Steven J.
AU - Riwanto, Meliana
AU - Manz, Jasmin
AU - Hubbard, Brian
AU - Tietjen, Ian
AU - Wong, Kenny
AU - Mitnaul, Lyndon J.
AU - Van Heek, Margaret
AU - Lin, Linus
AU - Roddy, Thomas A.
AU - McEwen, Jason
AU - Dallinge-Thie, Geesje
AU - Van Vark-Van Der Zee, Leonie
AU - Verwoert, Germaine
AU - Winther, Michael
AU - Van Duijn, Cornelia
AU - Hofman, Albert
AU - Trip, Mieke D.
AU - Marais, A. David
AU - Asztalos, Bela
AU - Landmesser, Ulf
AU - Sijbrands, Eric
AU - Kastelein, John J.
AU - Hayden, Michael R.
PY - 2013/2
Y1 - 2013/2
N2 - 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.
AB - 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.
KW - Cardiovascular disease
KW - Genetics
KW - High-density lipoprotein cholesterol
KW - Lipids
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U2 - 10.1161/CIRCGENETICS.111.962613
DO - 10.1161/CIRCGENETICS.111.962613
M3 - Review article
C2 - 23243195
AN - SCOPUS:84878041582
SN - 1942-325X
VL - 6
SP - 54
EP - 62
JO - Circulation: Cardiovascular Genetics
JF - Circulation: Cardiovascular Genetics
IS - 1
ER -