title: Loss-of-function variants in endothelial lipase are a cause of elevated HDL cholesterol in humans.
abstract: Elevated plasma concentrations of HDL cholesterol (HDL-C) are associated with protection from atherosclerotic cardiovascular disease. Animal models indicate that decreased expression of endothelial lipase (LIPG) is inversely associated with HDL-C levels, and genome-wide association studies have identified LIPG variants as being associated with HDL-C levels in humans. We hypothesized that loss-of-function mutations in LIPG may result in elevated HDL-C and therefore performed deep resequencing of LIPG exons in cases with elevated HDL-C levels and controls with decreased HDL-C levels. We identified a significant excess of nonsynonymous LIPG variants unique to cases with elevated HDL-C. In vitro lipase activity assays demonstrated that these variants significantly decreased endothelial lipase activity. In addition, a meta-analysis across 5 cohorts demonstrated that the low-frequency Asn396Ser variant is significantly associated with increased HDL-C, while the common Thr111Ile variant is not. Functional analysis confirmed that the Asn396Ser variant has significantly decreased lipase activity both in vitro and in vivo, while the Thr111Ile variant has normal lipase activity. Our results establish that loss-of-function mutations in LIPG lead to increased HDL-C levels and support the idea that inhibition of endothelial lipase may be an effective mechanism to raise HDL-C.
authors.affiliation: Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6160, USA.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Edmondson
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Brown
authors.forename: Sekar
authors.initials: S
authors.lastname: Kathiresan
authors.forename: L Adrienne
authors.initials: LA
authors.lastname: Cupples
authors.forename: Serkalem
authors.initials: S
authors.lastname: Demissie
authors.forename: Alisa Knodle
authors.initials: AK
authors.lastname: Manning
authors.forename: Majken K
authors.initials: MK
authors.lastname: Jensen
authors.forename: Eric B
authors.initials: EB
authors.lastname: Rimm
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Amrith
authors.initials: A
authors.lastname: Rodrigues
authors.forename: Vaneeta
authors.initials: V
authors.lastname: Bamba
authors.forename: Sumeet A
authors.initials: SA
authors.lastname: Khetarpal
authors.forename: Megan L
authors.initials: ML
authors.lastname: Wolfe
authors.forename: Stephanie
authors.initials: S
authors.lastname: Derohannessian
authors.forename: Mingyao
authors.initials: M
authors.lastname: Li
authors.forename: Muredach P
authors.initials: MP
authors.lastname: Reilly
authors.forename: Jens
authors.initials: J
authors.lastname: Aberle
authors.forename: David
authors.initials: D
authors.lastname: Evans
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hegele
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
mesh_terms: D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D000818:Animals; D050197:Atherosclerosis / Q000097:blood / Q000201:enzymology / Q000209:etiology / Q000235:genetics; D008076:Cholesterol, HDL / Q000097:blood*; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D005091:Exons; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008049:Lipase / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D017384:Sequence Deletion
chemical_list: D008076:Cholesterol, HDL; C410382:LIPG protein, human; D008049:Lipase