Interaction between SNPs in the RXRA and near ANGPTL3 gene region inhibits apoB reduction after statin-fenofibric acid therapy in individuals with mixed dyslipidemia

TitleInteraction between SNPs in the RXRA and near ANGPTL3 gene region inhibits apoB reduction after statin-fenofibric acid therapy in individuals with mixed dyslipidemia
Publication TypeJournal Article
Year of Publication2012
AuthorsMa L, Ballantyne CM, Belmont JW, Keinan A, Brautbar A
JournalJ. Lipid Res.
Volume53
Pagination2425–2428
ISSN0022-2275
KeywordsAngiopoietins, Apolipoproteins, Apolipoproteins B, Dyslipidemias, Female, Fenofibrate, Fluorobenzenes, Heptanoic Acids, Humans, Hydroxymethylglutaryl-{CoA} Reductase Inhibitors, Male, Polymorphism, Pyrimidines, Pyrroles, Simvastatin, Single Nucleotide, Sulfonamides
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.

URLhttp://keinanlab.cb.bscb.cornell.edu/sites/default/files/papers/ma_etal_2012_interactionbetweensnps_jlipidres.pdf
DOI10.1194/jlr.M028829