Loss-of-function variants in endothelial lipase are a cause of elevated HDL cholesterol in humans
View/ Open
Author
Edmondson, Andrew C.
Brown, Robert J.
Kathiresan, Sekar
Cupples, L. Adrienne
Demissie, Serkalem
Manning, Alisa Knodle
Jensen, Majken K.
Rimm, Eric Bruce::0ab2926c8242f35e5a982e3cf59f4987::600
Wang, Jian
Rodrigues, Amrith
Bamba, Vaneeta
Khetarpal, Sumeet A.
Wolfe, Megan L.
DerOhannessian, Stephanie
Li, Mingyao
Reilly, Muredach P.
Aberle, Jens
Evans, David
Hegele, Robert A.
Rader, Daniel J.
Published Version
https://doi.org/10.1172/JCI37176Metadata
Show full item recordCitation
Edmondson, Andrew C., Robert J. Brown, Sekar Kathiresan, L. Adrienne Cupples, Serkalem Demissie, Alisa Knodle Manning, Majken K. Jensen, Eric Rimm, et al. 2009. “Loss-of-Function Variants in Endothelial Lipase Are a Cause of Elevated HDL Cholesterol in Humans.” Journal of Clinical Investigation, March. https://doi.org/10.1172/jci37176.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.Terms of Use
This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAACitable link to this page
http://nrs.harvard.edu/urn-3:HUL.InstRepos:41263119
Collections
- SPH Scholarly Articles [6399]
Contact administrator regarding this item (to report mistakes or request changes)