ABSTRACT
Lipid-lowering therapy has shown a high degree of variability in clinical response and there is evidence that the variability in drug response between individuals is due to genetic factors. Thirteen single nucleotide polymorphisms (SNPs) within the ESR1 gene were evaluated with basal lipid and lipoprotein levels, as well as response to lipid-lowering therapy, in 495 hypercholesterolemic individuals of European descent receiving simvastatin or atorvastatin. Significant associations were detected between rs4870061 (P=0.040, corrected P-value (PC)=0.440), rs1801132 (P=0.002, PC=0.022) and the SNP rs3020314 (P=0.013, PC=0.143) with triglyceride (TG) baseline levels. The rs4870061 was also associated with high-density lipoprotein cholesterol (HDL-C) baseline levels (P=0.045, PC=0.495). Regarding statin efficacy, rs2234693 C/C was associated with greater HDL-C increase (P=0.037; PC=0.407) and rs3798577 T allele was associated with greater total cholesterol (TC) reduction (P=0.019; PC=0.209) and greater TG reduction (P=0.026; PC=0.286). These associations suggest that ESR1 polymorphisms are in part responsible for the TC, HDL-C and TG variation levels and this effect may be sex-specific.
Subject(s)
Atorvastatin/therapeutic use , Estrogen Receptor alpha/genetics , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hypercholesterolemia/drug therapy , Lipids/blood , Pharmacogenomic Variants , Polymorphism, Single Nucleotide , Simvastatin/therapeutic use , Aged , Biomarkers/blood , Brazil , Female , Gene Frequency , Haplotypes , Humans , Hypercholesterolemia/blood , Hypercholesterolemia/genetics , Linkage Disequilibrium , Male , Middle Aged , Pharmacogenetics , Phenotype , Prospective Studies , Sex Factors , Treatment OutcomeABSTRACT
We investigated the effect of single-nucleotide polymorphisms in sterol regulatory element-binding factors-1a and -2 (SREBF-1a and SREBF-2) and SREBF cleavage-activating protein (SCAP) genes on lipid-lowering response to simvastatin. In all, 146 hypercholesterolemic patients of European descent were prospectively treated with simvastatin 20 mg/day for over 6 months. Of these 99 subjects completed the 6-month follow-up. Plasma lipids and lipoproteins were measured before and throughout the study. The mean percentage decrease in plasma total cholesterol (TC) was greater in subject carriers of SCAP 2386G allele compared with those homozygous for 2386A allele (-29.6+/-13.4 vs -22.1+/-13.8%, P=0.007). About 61% of the 2386G carriers were above-average responders for TC levels (DeltaTC -27.8%), whereas only 29% of 2386A homozygous reached this reduction (P=0.009). Our data suggest that the SCAP 2386A>G gene polymorphism was a significant predictor of TC and triglyceride responses to simvastatin treatment.
