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

Ariel Brautbar,Maja Barbalic,Fengju Chen,John Belmont,Salim S Virani,Steve Scherer,Robert A Hegele,Christie M Ballantyne

doi:10.1194/jlr.m034132

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 fenofibric 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 fenofibric 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 fenofibric 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 fenofibric acid monotherapy or combined with statins.

Highlights

Individuals with mixed dyslipidemia, including high triglycerides (TGs) and low high density lipoprotein cholesterol (HDL-C), have increased risk for coronary events
Fibrates, including fenofibric acid, increase HDL-C and apolipoprotein A-I and decrease TGs in individuals with mixed dyslipidemia who are at increased risk for coronary heart disease [5,6,7,8]
We examined the association between rare genetic variants in the APOA5 gene region and change in HDL-C, apolipoprotein A-I (apoA-I), and TG levels in response to FA alone and in combination with statins

Summary

Introduction

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 fenofibric acid monotherapy and in combination with statins. Further study is needed to examine the effect of these rare variants on coronary outcomes in this population in response to fenofibric acid monotherapy or combined with statins.—Brautbar, A., M. Fibrates, including fenofibric 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 [5,6,7,8]. Fenofibric acid is a peroxisome proliferator-activated receptor-␣ (PPAR-␣) agonist, and Abbreviations: BMI, body mass index; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; PPAR-␣, peroxisome proliferator-activated receptor-␣; PPRE, peroxisome proliferator-response element; rHDL-C, residual high density lipoprotein cholesterol; SNP, single nucleotide polymorphism; TG, triglyceride; UTR, untranslated region

Methods

Results

Conclusion