Abstract
The mixed dyslipidemia phenotype is characterized by elevated triglycerides (TG), low HDL cholesterol (HDL-C), increased ApoB levels, and premature coronary atherosclerosis. Fibrate-statin combination therapy reduces ApoB levels and coronary events in the mixed dyslipidemia population. We sought to identify gene-gene interactions that affect ApoB response to statin-fenofibric acid therapy in the mixed dyslipidemia population. Using a predefined subset of single-nucleotide polymorphisms (SNPs) that were previously associated with TG, VLDL, or HDL-C, we applied gene-gene interaction testing in a randomized, double-blind, clinical trial examining the response to fenofibric acid (FNA) and its combination with statin in 1,865 individuals with mixed dyslipidemia. Of 11,783 possible SNP pairs examined, we detected a single significant interaction between rs12130333, located within the ANGPTL3 gene region, and rs4240705, within the RXRA gene, on ApoB reduction after statin-FNA therapy (P = 4.0 × 10(-6)). ApoB response to therapy gradually reduced with the increasing number of T alleles in the rs12130333 but only in the presence of the GG genotype of rs4240705. Individuals doubly homozygous for the minor alleles at rs12130333 and rs4240705 showed a paradoxical increase of 1.8% in ApoB levels after FNA-statin combination therapy. No gene-gene interaction was identified other than an interaction between SNPs in the ANGPTL3 and RXRA regions, which results in the inhibition of ApoB reduction in response to statin-FNA therapy. Further study is required to examine the clinical applicability of this genetic interaction and its effect on coronary events.
Highlights
The mixed dyslipidemia phenotype is characterized by elevated triglycerides (TG), low HDL cholesterol (HDL-C), increased ApoB levels, and premature coronary atherosclerosis
Examining the ApoB response of each of the nine genotype combinations of the two singlenucleotide polymorphism (SNP) suggests that the double homozygotes for the minor allele for each of the two SNPs is expected to exhibit an average increase in APOB, paradoxical to the expected drug response (Fig. 1)
We examined multiple gene-gene interactions between multiple candidate genes associated with ApoB, HDL-C, and TG with identifying a single novel interaction between the alleles in the RXRA and ANGPTL3 gene regions
Summary
The mixed dyslipidemia phenotype is characterized by elevated triglycerides (TG), low HDL cholesterol (HDL-C), increased ApoB levels, and premature coronary atherosclerosis. We sought to identify gene-gene interactions that affect ApoB response to statin-fenofibric acid therapy in the mixed dyslipidemia population. Using a predefined subset of single-nucleotide polymorphisms (SNPs) that were previously associated with TG, VLDL, or HDL-C, we applied gene-gene interaction testing in a randomized, doubleblind, clinical trial examining the response to fenofibric acid (FNA) and its combination with statin in 1,865 individuals with mixed dyslipidemia. Interaction between SNPs in the RXRA and near ANGPTL3 gene region inhibits apoB reduction after statin-fenofibric acid therapy in individuals with mixed dyslipidemia. Among the factors that determine the individual response to FNA and its combination with statins are single nucleotide polymorphisms (SNPs), which were previously shown to affect HDL-C, TG, and APOC-III levels in response to fibrates and statins [2,3,4]. We focused on a small set of SNPs that we identified as known to be highly relevant to the mixed dyslipidemia phenotype
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