The impact of partial and complete loss-of-function mutations in endothelial lipase on high-density lipoprotein levels and functionality in humans.
Singaraja RR., Sivapalaratnam S., Hovingh K., Dubé M-P., Castro-Perez J., Collins HL., Adelman SJ., Riwanto M., Manz J., Hubbard B., Tietjen I., Wong K., Mitnaul LJ., van Heek M., Lin L., Roddy TA., McEwen J., Dallinge-Thie G., van Vark-van der Zee L., Verwoert G., Winther M., van Duijn C., Hofman A., Trip MD., Marais AD., Asztalos B., Landmesser U., Sijbrands E., Kastelein JJ., Hayden MR.
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.