Variants in the APOA5 gene region and the response to combination therapy with statins and fenofibric acid in a randomized clinical trial of individuals with mixed dyslipidemia.

Abstract

OBJECTIVE:

Atherogenic dyslipidemia is highly associated with coronary heart disease and is characterized by elevated triglycerides (TG), low high-density lipoprotein cholesterol (HDL-C), and elevated low-density lipoprotein cholesterol (LDL-C). The combination of statins and fibrates is a common modality to treat individuals with atherogenic dyslipidemia. We sought to identify single nucleotide polymorphisms (SNPs) associated with HDL-C, TG, and apolipoprotein A1 (ApoA-I) response to combination therapy with statins and fenofibric acid (FA) in individuals with atherogenic dyslipidemia.

METHODS:

2228 individuals with mixed dyslipidemia who were participating in a multicenter, randomized, double-blind, active-controlled study comparing FA alone, in combination with a statin, or statin alone for a 12-week period, were genotyped for 304 candidate SNPs. A multivariate linear regression analysis for percent change in HDL-C, ApoA-I and TG levels was performed.

RESULTS:

SNPs in the apolipoprotein (APO) A5-ZNF259 region rs3741298 (P = 1.8 × 10(-7)), rs964184 (P = 3.6 × 10(-6)), rs651821 (P = 4.5 × 10(-5)), and rs10750097 (P = 1 × 10(-4)), were significantly associated with HDL-C response to combination therapy with statins and FA, with a similar association identified for ApoA-I. A haplotype composed of the minor alleles of SNPs rs3741298, rs964184, and rs10750097, was associated with a positive response to statins and FA (P = 8.7 × 10(-7)) and had a frequency of 18% in the study population.

CONCLUSION:

In a population with atherogenic dyslipidemia, common SNPs and haplotypes within the APOA5-ZNF259 region are highly associated with HDL-C and ApoA-I response to combination therapy with statins and FA.

• Authors: Ariel Brautbar, Daniel Covarrubias, John Belmont, Fremiet Lara-Garduno, Salim S Virani, Peter H Jones, Suzanne M Leal, Christie M Ballantyne
• Journal: Atherosclerosis (Atherosclerosis) Vol. 219 Issue 2 Pg. 737-42 (Dec 2011) ISSN: 1879-1484 [Electronic] Ireland
• PMID: 21889769 (Publication Type: Clinical Trial, Phase III, Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• APOA1 protein, human
• APOA5 protein, human
• Apolipoprotein A-I
• Apolipoprotein A-V
• Apolipoproteins A
• Biomarkers
• Cholesterol, HDL
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Hypolipidemic Agents
• Triglycerides
• Fenofibrate

Topics

• Apolipoprotein A-I (blood)
• Apolipoprotein A-V
• Apolipoproteins A (genetics)
• Biomarkers (blood)
• Cholesterol, HDL (blood)
• Double-Blind Method
• Drug Therapy, Combination
• Dyslipidemias (blood, drug therapy, genetics)
• Female
• Fenofibrate (therapeutic use)
• Gene Frequency
• Genetic Predisposition to Disease
• Haplotypes
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (therapeutic use)
• Hypolipidemic Agents (therapeutic use)
• Linear Models
• Male
• Multivariate Analysis
• Phenotype
• Polymorphism, Single Nucleotide
• Prospective Studies
• Time Factors
• Treatment Outcome
• Triglycerides (blood)