Impact of CYP3A5 Gene Polymorphism on Efficacy of Simvastatin

Abstract

Background: One of the promises of human genetics is individualized therapy. Therefore, we evaluated the impact of CYP3A5 gene polymorphism on the effectiveness of simvastatin (a HMG-CoA reductase inhibitor). Methods: Patients (n = 191) with hypercholesterolemia were treated with simvastatin for at least 6 months and were genotyped for the CYP3A5 polymorphism. Results: The frequency of CYP3A5 polymorphism was 0.5% for WT (wild-type), 15.6% for HT (heterozygous, expressors) and 83.9% for HM (homozygous, non-expressors). Differences in lipid profile before and after dose-response of simvastatin treatment were described as % difference {[(variable after-variable before)/variable before]*100}. There was a trend towards the decrease of low density lipoprotein cholesterol (LDL-C) in HT individuals who had a -35.2% reduction with a dose of 20 mg simvastatin and HM individuals who had a slightly higher decrease (-37.5%) despite the lower dose of simvastatin (10 mg, p = 0.07). Furthermore, HT genotype individuals had significantly higher than expected (6-8%) LDL-C % difference between 20 and 40 mg of simvastatin (-35.2 vs -49.2%, p = 0.037). In individuals with HM genotype a significant LDL-C % difference was found between 10 and 40 mg of simvastatin (-37.5 vs -48.4%, p = 0.023). Conclusion: The individuals with HM polymorphism display a trend towards higher LDL-C reductions compared with HT polymorphism. Within the same genotype, differences between doses were also observed. These findings need to be confirmed in larger studies.

Genetic Variation in the UGT1A Locus is Associated with Simvastatin Efficacy in a Clinical Practice Setting

“…The association between simvastatin efficacy and rs776746 and a lack of association with rs4149056 has been reported by others [25,26]. It is, thus, possible that our findings with UGT1A1 variants are driven by an interaction with a variant in these other PK candidate genes.…”

Frequency of CYP450 enzyme gene polymorphisms in the Greek population: review of the literature, original findings and clinical significance

“…The results of a study of CYP3AP1 pseudogene -44G > A polymorphism with statin response in a patient cohort consisted of 202 simvastatin-treated and 177 atorvastatin treated Chinese hyperlipidemic patients also showed that in the simvastatin treatment group, the percentage reduction of LDL-C was greater in female CYP3AP1*3/*3 carriers than CYP3AP1*1 carriers [82]. In the Greek population, in a more recent study in 191 simvastatin treated patients, Kolovou et al have shown that CYP3A5 non-expressors display a trend towards higher LDL-C reductions compared with CYP3A5 expressors [83]. In this study, the frequency of CYP3A5 expressors was estimated at 15.6%, in accordance with the prevalence already reported for the Greek population.…”

Microsomal Transfer Protein Inhibitors, New Approach for Treatment of Familial Hypercholesterolemia, Review of the Literature, Original Findings, and Clinical Significance

“…The drugs in use include pitavastatin, rosuvastatin, atorvastatin, simvastatin, fluvastatin, pravastatin, and lovastatin. There is considerable variation in the statin lowering response of LDL cholesterol (À25 to 60%) [45,46]. Genetic determinants of responsiveness to the statins cannot be excluded [47].…”