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

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

doi:10.1194/jlr.m020404

Abstract

ApoC-III is a proatherogenic protein associated with elevated triglycerides; its deficiency is associated with reduced atherosclerosis. Mixed dyslipidemia, characterized by elevated triglyceride and apoC-III levels and low HDL cholesterol level, with or without elevated LDL cholesterol, increases cardiovascular disease risk and is commonly treated with combined statin and fibrate therapy. We sought to identify single nucleotide polymorphisms (SNPs) associated with apoC-III level response to combination therapy with statins and fenofibric acid (FA) in individuals with mixed dyslipidemia. Participants (n = 1,250) in a multicenter, randomized, double-blind, active-controlled study examining response to FA alone and in combination with statin were genotyped for candidate SNPs. Multivariate linear regression and two-way ANOVA for percent change in apoC-III level were performed. SNPs in the lipoprotein lipase (LPL) gene region, rs1801177 (P = 4.7 × 10(-8)), rs7016529 (P = 1.2 × 10(-6)), and rs249 (P = 4.1 × 10(-5)), were associated with apoC-III response to combination therapy. A haplotype composed of the minor alleles of these SNPs, with 2% population frequency, was associated with an unexpected apoC-III increase in response to statins and FA. This is the first report to show that genetic variation within the LPL gene region can affect the response of apoC-III levels to combined statin and FA therapy.

Highlights

ApoC-III is a proatherogenic protein associated with elevated triglycerides; its deficiency is associated with reduced atherosclerosis
We examined the association between single-nucleotide polymorphisms (SNPs) and change in Abbreviations: CHD, coronary heart disease; FA, fenofibric acid; HDL-C, HDL-cholesterol; LD, linkage disequilibrium; LDL-C, LDLcholesterol; MAF, minor allele frequency; SNP, single-nucleotide polymorphism; TG, triglyceride
No significant associations were identified in the FA-only and statin-only groups between SNPs and percent change in apoC-III level in response to therapy (Table 1). rs249 and rs7016529 reside within introns of the lipoprotein lipase (LPL) gene, whereas rs1801177 is a missense mutation in exon 2 that results in a nonconservative substitution of asparagine for aspartic acid

Summary

Introduction

ApoC-III is a proatherogenic protein associated with elevated triglycerides; its deficiency is associated with reduced atherosclerosis. Mixed dyslipidemia, characterized by elevated triglyceride and apoC-III levels and low HDL cholesterol level, with or without elevated LDL cholesterol, increases cardiovascular disease risk and is commonly treated with combined statin and fibrate therapy. We sought to identify single nucleotide polymorphisms (SNPs) associated with apoC-III level response to combination therapy with statins and fenofibric acid (FA) in individuals with mixed dyslipidemia. A haplotype composed of the minor alleles of these SNPs, with 2% population frequency, was associated with an unexpected apoCIII increase in response to statins and FA This is the first report to show that genetic variation within the LPL gene region can affect the response of apoC-III levels to combined statin and FA therapy.—Brautbar, A., S. 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. We examined the association between single-nucleotide polymorphisms (SNPs) and change in Abbreviations: CHD, coronary heart disease; FA, fenofibric acid; HDL-C, HDL-cholesterol; LD, linkage disequilibrium; LDL-C, LDLcholesterol; MAF, minor allele frequency; SNP, single-nucleotide polymorphism; TG, triglyceride

Methods

Results

Conclusion