Interaction between SNPs in the RXRA and near ANGPTL3 gene region inhibits apoB reduction after statin-fenofibric acid therapy in individuals with mixed dyslipidemia.
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.
Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, NY, USA.
Li
L
Ma
Christie M
CM
Ballantyne
John W
JW
Belmont
Alon
A
Keinan
Ariel
A
Brautbar
D000091303:Angiopoietin-Like Protein 3; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000235:genetics*; D001053:Apolipoproteins / Q000378:metabolism*; D001055:Apolipoproteins B / Q000378:metabolism*; D000069059:Atorvastatin; D050171:Dyslipidemias / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D011345:Fenofibrate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005464:Fluorobenzenes / Q000627:therapeutic use; D006538:Heptanoic Acids / Q000627:therapeutic use; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011743:Pyrimidines / Q000627:therapeutic use; D011758:Pyrroles / Q000627:therapeutic use; D000068718:Rosuvastatin Calcium; D019821:Simvastatin / Q000627:therapeutic use; D013449:Sulfonamides / Q000627:therapeutic use
C479896:ANGPTL3 protein, human; D000091303:Angiopoietin-Like Protein 3; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; D001053:Apolipoproteins; D001055:Apolipoproteins B; D005464:Fluorobenzenes; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D000069059:Atorvastatin; D019821:Simvastatin; C006012:fenofibric acid; D011345:Fenofibrate