Loss-of-function variants in endothelial lipase are a cause of elevated HDL cholesterol in humans.
Standard
Loss-of-function variants in endothelial lipase are a cause of elevated HDL cholesterol in humans. / Edmondson, Andrew C; Brown, Robert J; Kathiresan, Sekar; Cupples, L Adrienne; Demissie, Serkalem; Manning, Alisa Knodle; Jensen, Majken K; Rimm, Eric B; 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.
In: J CLIN INVEST, Vol. 119, No. 4, 4, 2009, p. 1042-1050.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Loss-of-function variants in endothelial lipase are a cause of elevated HDL cholesterol in humans.
AU - Edmondson, Andrew C
AU - Brown, Robert J
AU - Kathiresan, Sekar
AU - Cupples, L Adrienne
AU - Demissie, Serkalem
AU - Manning, Alisa Knodle
AU - Jensen, Majken K
AU - Rimm, Eric B
AU - Wang, Jian
AU - Rodrigues, Amrith
AU - Bamba, Vaneeta
AU - Khetarpal, Sumeet A
AU - Wolfe, Megan L
AU - Derohannessian, Stephanie
AU - Li, Mingyao
AU - Reilly, Muredach P
AU - Aberle, Jens
AU - Evans, David
AU - Hegele, Robert A
AU - Rader, Daniel J
PY - 2009
Y1 - 2009
N2 - 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.
AB - 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.
M3 - SCORING: Zeitschriftenaufsatz
VL - 119
SP - 1042
EP - 1050
JO - J CLIN INVEST
JF - J CLIN INVEST
SN - 0021-9738
IS - 4
M1 - 4
ER -