Loss-of-function variants in endothelial lipase are a cause of elevated HDL cholesterol in humans

Edmondson, Andrew C.; Brown, Robert; Kathiresan, Sekar; Cupples, L. Adrienne; Demissie, Serkalem; Manning, Alisa K.; 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 M.; Hegele, Robert A.; Rader, Daniel J.

doi:10.1172/jci37176

Cited by 116 publications

(169 citation statements)

References 60 publications

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“…Other than CETP, LIPC and LPL are responsible for elevated HDL-C level, and T allele of LIPC gene -514C/T polymorphism and 447X allele of LPL gene S447X polymorphism are well known to both cause 3 mg/dL of elevated HDL-C levels in Japanese (LIPC -514T allele: 75%, LPL 447X allele: 22% in Japanese population) [22,23]. If subjects who have a heterozygote of CETP mutation but rather high levels of HDL-C, further analysis involving endothelial lipase [24] and scavenger receptor class B type I (SR-BI) [25,26] activities is needed.…”

Section: Discussionmentioning

confidence: 99%

Novel mutations of cholesteryl ester transfer protein (CETP) gene in Japanese hyperalphalipoproteinemic subjects

Ohtani

Inazu

Noji

et al. 2012

Clinica Chimica Acta

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Background: The half of hyperalphalipoproteinemia (HALP) in Japan is caused by CETP gene mutations. Other than two prevalent mutations (D442G and Intron 14 splicing donor site +1 G>A), some rare CETP mutations are found in Japanese HALP subjects.Methods: CETP gene analysis of genomic DNA from subjects was performed by restriction fragment length polymorphism (RFLP) and sequencing analysis. Mutations which were suspected to cause a splicing defect or a protein secretion defect were investigated in COS-1 cells transfected with a CETP minigene construct or a cDNA expression vector.Results: Each of three subjects was identified as a carrier of CETP gene mutation of a compound heterozygote of c.653_654delGGinsAAAC and Intron 14 splicing donor site +1 G>A, a heterozygote of c.658G>A or a homozygote of L261R. The c.658G>A mutation was located at the last nucleotide of exon 7, and it was confirmed to cause splicing abnormality revealed by the CETP minigene analysis. The L261R CETP was not secreted to conditioned media of the cells.Conclusions: Three novel CETP gene mutations are responsible for HALP by CETP deficiency. It is predicted that there are more rare CETP gene mutations in Japanese, and these multiple rare mutations alone or a combination with each of prevalent mutations responsible for mild-to-moderate or marked HALP, respectively.3

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Section: Discussionmentioning

confidence: 99%

Novel mutations of cholesteryl ester transfer protein (CETP) gene in Japanese hyperalphalipoproteinemic subjects

Ohtani

Inazu

Noji

et al. 2012

Clinica Chimica Acta

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“…Recent evidence implies that the presence of the EL 584C/T gene polymorphism (rs2000813) is correlated to the plasma HDL-C level (Hutter et al, 2006). Edmondson et al (2009) found that the level of HDL-C increases in the loss-of-function variants of EL, and concluded that inhibition of EL may, therefore, raise the HDL-C level. In 2003, Ma et al reported that patients with the TT genotype have higher HDL-C levels than those with the CC genotype.…”

Section: Introductionmentioning

confidence: 99%

Lack of association between a common polymorphism of the endothelial lipase gene and early-onset coronary artery disease in a Chinese Han population

Cai¹,

He²,

Huang³

et al. 2014

Genet. Mol. Res.

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ABSTRACT.A growing body of evidence suggests that the 584C/T polymorphism in the endothelial lipase (EL) gene contributes to the process of coronary artery disease (CAD). The present study aimed to reveal the potential relationship between the EL 584C/T gene polymorphism and early-onset CAD, CAD severity, and lipid levels in a Chinese Han population. Participants comprised 135 early-onset CAD patients and 166 controls. EL 584C/T genotypic and allelic frequencies were detected by PCR. The frequencies of the CC, CT, and TT genotypes were 58.4, 38.6, and 3.0%, respectively, within the control group, and 62.2, 33.3, and 4.5%, respectively, in the early-onset CAD group. There was no significant difference in the frequency of CC genotype and T allele carriers between early-onset CAD patients and controls. The frequency of the T allele was 22.3% in the control group and 21.1% in the early-onset CAD group. The T allele frequency of the variant was not significantly different between the two groups (P = 0.766), even after adjustments for age, gender, smoking status, hypertension, DM, and lipids were made. There was also no significant association between the genotype and the severity of CAD (P = 0.596). Furthermore, there was no correlation between the genotype and lipid levels or their ratios in both groups. The EL 584C/T gene polymorphism, therefore, was not associated with early-onset CAD or the severity of CAD in this Chinese Han population, suggesting that this variant is not always involved in the pathogenesis of early-onset CAD.

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“…Previous studies have shown that plasma EL mass measured by ELISA is inversely correlated with HDL-C concentrations in humans (15,16 ). Association-based human genetic studies have provided evidence that variations in the EL genomic LIPG locus such as T111I, G26S, and N396S are linked to differences in circulating HDL-C concentrations or CVD (17)(18)(19)(20)(21), although recent studies with a large number of subjects have established associations between LIPG single-nucleotide polymorphism and HDL-C concentrations, but none with CVD (21)(22)(23). Thus, genetic variation in EL can modulate plasma HDL-C concentrations, although the relationship with CVD remains controversial.…”

mentioning

confidence: 99%

ELISA System for Human Endothelial Lipase

et al. 2012

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BACKGROUND Endothelial lipase (EL) regulates the metabolism of HDL cholesterol (HDL-C). However, the role of EL in regulating plasma HDL-C concentrations and EL's potential involvement in atherosclerosis in humans has not been fully investigated due to the lack of reliable assays for EL mass. We developed an ELISA system for serum EL mass. METHODS Human recombinant EL proteins, purified from cultured media of human EL–transfected Chinese hamster ovary cells, were used as antigen and calibrator. Two specific monoclonal antibodies were generated in mice against recombinant EL protein for a sandwich ELISA. We measured EL mass in human serum using EL recombinant protein as a calibration standard. RESULTS The EL antibodies did not cross-react with lipoprotein lipase and hepatic triglyceride lipase. The detection limit of the ELISA was 20 pg/mL, which is approximately 10 times lower than that of previous ELISA systems. Recovery of spiked EL in serum was 90%–105%. Assay linearity was intact with a >4-fold dilution of serum. Intra- and interassay CVs were <5%. The serum EL mass in 645 human subjects was [mean (SE)] 344.4 (7.7) pg/mL (range 55.2–1387.7 pg/mL). Interestingly, serum EL mass was increased in patients with diagnosed cardiovascular disease and inversely correlated with serum HDL-C concentrations. There was no difference in EL mass between pre- and postheparin plasma samples. CONCLUSIONS This ELISA should be useful for clarifying the impact of EL on HDL metabolism and EL's potential role in atherosclerosis.

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Loss-of-function variants in endothelial lipase are a cause of elevated HDL cholesterol in humans

Cited by 116 publications

References 60 publications

Novel mutations of cholesteryl ester transfer protein (CETP) gene in Japanese hyperalphalipoproteinemic subjects

Novel mutations of cholesteryl ester transfer protein (CETP) gene in Japanese hyperalphalipoproteinemic subjects

Lack of association between a common polymorphism of the endothelial lipase gene and early-onset coronary artery disease in a Chinese Han population

ELISA System for Human Endothelial Lipase

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