LPL gene variants affect apoC-III response to combination therapy of statins and fenofibric acid in a randomized clinical trial of individuals with mixed dyslipidemia

Brautbar, Ariel; Virani, Salim S.; Belmont, John W.; Nambi, Vijay; Jones, Peter H.; Ballantyne, Christie M.

doi:10.1194/jlr.m020404

Cited by 12 publications

(9 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In recent studies, SNPs in the APOA5 gene region were shown to be signifi cantly associated with both HDL-C and TG response to fi brate monotherapy or in combination with statins (10)(11)(12)(13). In this study, we examined the association between rare genetic variants in the APOA5 gene region and change in HDL-C, apoA-I, and TG levels in response to FA alone and in combination with statins.…”

Section: Resultsmentioning

confidence: 99%

Rare APOA5 promoter variants associated with paradoxical HDL cholesterol decrease in response to fenofibric acid therapy

Brautbar

Barbalić

Chen

et al. 2013

Journal of Lipid Research

Self Cite

View full text Add to dashboard Cite

Mixed dyslipidemia, which occurs frequently in individuals with insulin resistance, such as those with metabolic syndrome, is characterized by elevated triglycerides (TGs) and decreased high density lipoprotein cholesterol (HDL-C). Genome-wide association studies have demonstrated associations between common genetic variants and interindividual differences in serum TGs and HDL-C ( 1, 2 ). Rarer genetic variants, with frequency of less than 1%, discovered by DNA sequencing show a larger effect size on the respective quantitative traits ( 3, 4 ). An important potential application of common and rare variants is to improve prediction of individualized response to therapy and personalize therapy based on that information.Fibrates, including fenofi bric acid, increase HDL-C and apolipoprotein A-I (apoA-I) and decrease TGs in individuals with mixed dyslipidemia who are at increased risk for coronary heart disease ( 5-8 ). Fenofi bric acid is a peroxisome proliferator-activated receptor-␣ (PPAR-␣ ) agonist, and Abstract Individuals with mixed dyslipidemia, including high triglycerides (TGs) and low high density lipoprotein cholesterol (HDL-C), have increased risk for coronary events. We examined the effect of rare genetic variants in the APOA5 gene region on plasma HDL-C, apolipoprotein A-I (apoA-I), and TG response to fenofi bric acid monotherapy and in combination with statins. The APOA5 gene region was sequenced in 1,612 individuals with mixed dyslipidemia in a randomized trial of fenofi bric acid alone and in combination with statins. Student's t -test and rare variant burden tests were used to examine plasma HDL-C, apoA-I, and TG response. Rare APOA5 promoter region variants were associated with decreased HDL-C and apoA-I levels in response to fenofi bric acid therapy; rare missense variants were associated with increased TG response to combination therapy. Further study is needed to examine the effect of these rare variants on coronary outcomes in this population in response to fenofi bric acid monotherapy or combined with statins .-Brautbar, A

show abstract

Section: Resultsmentioning

confidence: 99%

Rare APOA5 promoter variants associated with paradoxical HDL cholesterol decrease in response to fenofibric acid therapy

Brautbar

Barbalić

Chen

et al. 2013

Journal of Lipid Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…In this study, we follow a similar approach by testing interactions between a focused set of SNPs in a Randomized Candidate Gene (RCG) study, in which the genes have been targeted as related to lipid and lipoprotein levels [13] , [23] . We identified and replicated one significant gene-gene interaction affecting HDL-C levels, which involves the exact same SNP as the one previously reported to be involved in a different gene-gene interaction underlying HDL-C levels [12] .…”

Section: Introductionmentioning

confidence: 99%

Analysis of Multiple Association Studies Provides Evidence of an Expression QTL Hub in Gene-Gene Interaction Network Affecting HDL Cholesterol Levels

Ballantyne²,

Brautbar³

et al. 2014

PLoS ONE

Self Cite

View full text Add to dashboard Cite

Epistasis has been suggested to underlie part of the missing heritability in genome-wide association studies. In this study, we first report an analysis of gene-gene interactions affecting HDL cholesterol (HDL-C) levels in a candidate gene study of 2,091 individuals with mixed dyslipidemia from a clinical trial. Two additional studies, the Atherosclerosis Risk in Communities study (ARIC; n = 9,713) and the Multi-Ethnic Study of Atherosclerosis (MESA; n = 2,685), were considered for replication. We identified a gene-gene interaction between rs1532085 and rs12980554 (P = 7.1×10−7) in their effect on HDL-C levels, which is significant after Bonferroni correction (P c = 0.017) for the number of SNP pairs tested. The interaction successfully replicated in the ARIC study (P = 7.0×10−4; P c = 0.02). Rs1532085, an expression QTL (eQTL) of LIPC, is one of the two SNPs involved in another, well-replicated gene-gene interaction underlying HDL-C levels. To further investigate the role of this eQTL SNP in gene-gene interactions affecting HDL-C, we tested in the ARIC study for interaction between this SNP and any other SNP genome-wide. We found the eQTL to be involved in a few suggestive interactions, one of which significantly replicated in MESA. Importantly, these gene-gene interactions, involving only rs1532085, explain an additional 1.4% variation of HDL-C, on top of the 0.65% explained by rs1532085 alone. LIPC plays a key role in the lipid metabolism pathway and it, and rs1532085 in particular, has been associated with HDL-C and other lipid levels. Collectively, we discovered several novel gene-gene interactions, all involving an eQTL of LIPC, thus suggesting a hub role of LIPC in the gene-gene interaction network that regulates HDL-C levels, which in turn raises the hypothesis that LIPC's contribution is largely via interactions with other lipid metabolism related genes.

show abstract

“…Serum TG is first hydrolyzed, which liberates FFA during TG catabolism 26 . Lipoprotein lipase (LPL) is the key enzyme that hydrolyzes circulating TG, delivering FFAs to peripheral tissues for utilization and storage 27 28 . In our study, serum TG was significantly decreased in the mangiferin supplementation group and serum LPL activity was significantly increased, which suggested that mangiferin at least partly increased TG hydrolysis by LPL, and the decrease in serum TG was due to the increase in serum TG catabolism.…”

Section: Discussionmentioning

confidence: 99%

Mangiferin supplementation improves serum lipid profiles in overweight patients with hyperlipidemia: a double-blind randomized controlled trial

Zhang

Jiang

et al. 2015

Sci Rep

View full text Add to dashboard Cite

Our previous studies have shown that mangiferin decreased serum triglycerides and free fatty acids (FFAs) by increasing FFAs oxidation in both animal and cell experiments. This study sought to evaluate the effects of mangiferin on serum lipid profiles in overweight patients with hyperlipidemia. Overweight patients with hyperlipidemia (serum triglyceride ≥ 1.70 mmol/L, and total cholesterol ≥ 5.2 mmol/L) were included in this double-blind randomized controlled trial. Participants were randomly allocated to groups, either receiving mangiferin (150 mg/day) or identical placebo for 12 weeks. The lipid profile and serum levels of mangiferin, glucose, L-carnitine, β-hydroxybutyrate, and acetoacetate were determined at baseline and 12 weeks. A total of 97 participants completed the trial. Compared with the placebo control, mangiferin supplementation significantly decreased the serum levels of triglycerides and FFAs, and insulin resistance index. Mangiferin supplementation also significantly increased the serum levels of mangiferin, high-density lipoprotein cholesterol, L-carnitine, β-hydroxybutyrate, and acetoacetate, and increased lipoprotein lipase activity. However, there were no differences in the serum levels of total cholesterol, low-density lipoprotein cholesterol, serum glucose, and insulin between groups. Mangiferin supplementation could improve serum lipid profiles by reducing serum triglycerides and FFAs in overweight patients with hyperlipidemia, partly due to the promotion of FFAs oxidation.

show abstract

LPL gene variants affect apoC-III response to combination therapy of statins and fenofibric acid in a randomized clinical trial of individuals with mixed dyslipidemia

Cited by 12 publications

References 29 publications

Rare APOA5 promoter variants associated with paradoxical HDL cholesterol decrease in response to fenofibric acid therapy

Rare APOA5 promoter variants associated with paradoxical HDL cholesterol decrease in response to fenofibric acid therapy

Analysis of Multiple Association Studies Provides Evidence of an Expression QTL Hub in Gene-Gene Interaction Network Affecting HDL Cholesterol Levels

Mangiferin supplementation improves serum lipid profiles in overweight patients with hyperlipidemia: a double-blind randomized controlled trial

Contact Info

Product

Resources

About