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

Abstract

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

Molecular mechanism of PPARα action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease

“…These findings are consistent with the identification of a functional PPRE in the human, but not mouse Apo-AV promoter [88,89]. In humans, rare SNPs in the APO-AV promoter region are associated with paradoxical decreases in plasma HDL-C and APO-AI in response to fibrates, whereas SNPs within the APO-AV gene are associated with enhanced lipid response to fibrate and statin therapy [90][91][92][93]. Thus, unexpected responses to fibrate treatment in some individuals may be due to genetic variations in PPARa target genes, such as APO-AV.…”

Differential Lipid Response to Statins Is Associated With Variants in the BUD13–APOA5 Gene Region

“…11,19,20 The same region was also shown in large genome-wide association studies to be associated with baseline triglyceride and HDL-C levels. One limitation of our study—inherent in the sample set—is that previous use of other drug groups (statins, fibrates, niacin) prior to initiating the drug under investigation was not accounted for in the analyses.…”

“…However, SNPs outside of the APOA5 region and promoters such as ZNF259 have been shown in prior studies to affect the response to statin-fibrate therapy. 11,19,20 It is possible that these SNPs affect APOA5 response to statins and, thus, the availability of TGs to be incorporated into lipoproteins such as low-density lipoprotein, very low-density lipoprotein, and chylomicrons.…”

Molecular cloning and structural characterization of PPARα gene from turbot ( Scophthalmus maximus ) and functional exploration of lipid metabolism in response to thermal stress

“…Therefore, lipid metabolism is fundamental to life. In mammals, the most notable role of PPARα is its involvement in lipid metabolism, including high‐ and low‐density lipoproteins, cholesterol, apolipoproteins, triglycerides, phospholipids and fatty acids (Brautbar et al, 2013; Lefebvre et al, 2006; Mandard et al, 2004). PPARα ‐null mice develop obesity and high plasma triglyceride levels, and they are more vulnerable to high‐fat diet‐induced nonalcoholic fatty liver disease (Abdelmegeed et al, 2011; Costet et al, 1998).…”