Maria Elvira Wagner Ferreira

The role of common variants of ABCB1, CYP3A4, and CYP3A5 genes in lipid‐lowering efficacy and safety of simvastatin treatment

Our objective was to investigate the interactions between common polymorphisms in ABCB1, CYP3A4, and CYP3A5 genes and the lipid‐lowering efficacy and safety of the 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase inhibitor simvastatin.

Determinants of variable response to simvastatin treatment: the role of common variants of SCAP , SREBF-1a and SREBF-2 genes

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 (ΔTC −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.

Evaluation of Sexual Dimorphism in the Efficacy and Safety of Simvastatin/Atorvastatin Therapy in a Southern Brazilian Cohort

Background Dyslipidemia is the primary risk factor for cardiovascular disease, and statins have been effective in controlling lipid levels. Sex differences in the pharmacokinetics and pharmacodynamics of statins contribute to interindividual variations in drug efficacy and toxicity. Objective To evaluate the presence of sexual dimorphism in the efficacy and safety of simvastatin/atorvastatin treatment. Methods Lipid levels of 495 patients (331 women and 164 men) were measured at baseline and after 6 ± 3 months of simvastatin/atorvastatin treatment to assess the efficacy and safety profiles of both drugs. Results Women had higher baseline levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) compared with men (p < 0.0001). After treatment, women exhibited a greater decrease in plasma TC and LDL-C levels compared with men. After adjustment for covariates, baseline levels of TC and LDL-C influenced more than 30% of the efficacy of lipid-lowering therapy (p < 0.001), regardless of sex. Myalgia [with or without changes in creatine phosphokinase (CPK) levels] occurred more frequently in women (25.9%; p = 0.002), whereas an increase in CPK and/or abnormal liver function was more frequent in in men (17.9%; p = 0.017). Conclusions Our results show that baseline TC and LDL-C levels are the main predictors of simvastatin/atorvastatin therapy efficacy, regardless of sex. In addition, they suggest the presence of sexual dimorphism in the safety of simvastatin/atorvastatin. The effect of sex differences on receptors, transporter proteins, and gene expression pathways needs to be better evaluated and characterized to confirm these observations.

Influence of PPARA, RXRA, NR1I2 and NR1I3 gene polymorphisms on the lipid-lowering efficacy and safety of statin therapy

OBJECTIVE The aim of the present study was investigate the association between six genetic variants in the nuclear receptor genes PPARA, RXRA, NR1I2 and NR1I3 and the lipid-lowering efficacy and safety of statin therapy. SUBJECTS AND METHODS The study was carried out on 240 Brazilian hypercholesterolemic patients on simvastatin and atorvastatin therapy. The polymorphisms were analyzed by PCR-based methods. RESULTS The NR1I3 rs2307424 genotype distribution was different between subjects with and without adverse drug reactions. Among subjects in the ADR group, no T/T homozygotes were observed for this polymorphism, while in the non-ADR group the frequency of this genotype was 19.4% (P = 0.007, after multiple testing corrections P = 0.042). CONCLUSION The polymorphisms investigated in PPARA (rs1800206), RXRA (rs11381416), and NR1I2 (rs1523130) did not influence the lipid-lowering efficacy and safety of statin. Our results show the possible influence of NR1I3 genetic variant on the safety of statin.

ESR1 polymorphisms and statin therapy: a sex-specific approach.

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.

PON1 polymorphisms are predictors of ability to attain HDL-C goals in statin-treated patients

OBJECTIVES PON1 plays an important role in inhibiting LDL-C oxidation, which reduces atherosclerosis and cardiovascular disease. Elevated PON1 activity or levels may contribute to increased HDL-C levels, but controversy exists over the hypothesis that genetic variation in the PON1 gene locus modulates HDL-C levels and responses to statin treatment. Therefore, the objective of this study was to investigate the association between two polymorphisms in the PON1 gene and statin responses in a south Brazilian population. DESIGN AND METHODS The study population included 433 dyslipidemic patients who were prescribed statins. Total cholesterol, triglyceride, HDL-C and LDL-C levels were measured in these patients both before and after approximately 6months of treatment with simvastatin/atorvastatin. Genotypes were assessed by real-time PCR for two PON1 polymorphisms, Q192R (rs662) and L55M (rs854560). RESULTS Baseline lipid levels were not associated with Q192R or L55M polymorphisms. For the Q192R (rs662) polymorphism, we observed that HDL-C goals were attained less often in patients with RR homozygosity than in Q allele carriers (χ(2) P=0.009, adjusted residual analysis P=0.003). For the L55M (rs854560) polymorphism, LL homozygotes were underrepresented among subjects that achieved the HDL-C goal (χ(2) P=0.026, adjusted residual analysis P=0.008). Analysis by univariate logistic regression confirmed that QQ/QR and MM/ML carriers had an increased chance of attaining HDL-C goals (OR=2.41, CI95%=1.32-4.40, P=0.004 and OR=1.68, CI95%=1.15-2.45, P=0.008). In a multivariate logistic analysis used to assess predictors of attaining an HDL-C goal>1.55mmol/L, we observed that gender (OR=1.71, CI95%=1.04-2.83, P=0.036), baseline HDL-C levels (OR=1.13, CI95%=1.10-1.16, P<0.001) and the QQ/QR+MM/ML genotypes increased the chance of achieving HDL-C goals (OR=2.81, CI95%=1.35-5.85, P=0.006). CONCLUSIONS The results of this study show that the Q192R (rs662) and L55M (rs854560) polymorphisms may play a role in interindividual variation in achievement of HDL-C goals in response to statins.