Identification of pharmacogenetic predictors of lipid-lowering response to atorvastatin in Chilean subjects with hypercholesterolemia

Ragia

et al. 2014

TOCMJ

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.

Section: Discussionsupporting

confidence: 67%

Impact of CYP3A5 Gene Polymorphism on Efficacy of Simvastatin

Ragia

et al. 2014

TOCMJ

“…The CYP3A4 M445T variant was associated with 6.4% lower LDL levels at the end of atorvastatin therapy, whereas the CYP3A4 A‐290G variant was associated with 12.4% higher LDL concentrations at the end of atorvastatin therapy (Table ) . Although percentage change measured in this study was not significantly associated with CYP3A4 genotypes, another study reported a statistically significant association of CYP3A4 A‐290G variant with percentage change in LDL from baseline . Furthermore, the CYP3A4 −290A>G variant allele compared with the wild‐type allele was associated with greater increase in HDL levels (p<0.001) .…”

Section: Atorvastatinmentioning

confidence: 53%

Impact of Pharmacogenetics on Efficacy and Safety of Statin Therapy for Dyslipidemia

et al. 2017

Interindividual variability in response to 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, with regard to both efficacy and safety is an obvious target for pharmacogenetic research. Many genes have been identified as possible contributors to variability in statin response and safety. Genetic polymorphisms may alter the structure or expression of coded proteins, with potential impacts on lipid and statin absorption, distribution, metabolism, and elimination as well as response pathways related to the pharmacologic effect. Many studies have explored the variation in statins' pharmacokinetic and pharmacodynamic parameters; however, to our knowledge, few have established definitive relationships between the genetic polymorphisms and patient outcomes, such as cardiovascular events. In this review article, we provide a statin-based summary of available evidence describing pharmacogenetic associations that may be of clinical relevance in the future. Although currently available studies are often small or retrospective, and may have conflicting results, they may be useful in providing direction for future confirmatory studies and may point to associations that could be confirmed in the future when more patient outcomes-based studies are available. We also summarize the clinically relevant evidence currently available to assist clinicians with providing personalized pharmacotherapy for patients requiring statin therapy.

“…A genome-wide association study shows associations of LDL-c response to atorvastatin with polymorphisms in LPA and APOE genes (Deshmukh et al 2012). The CYP7A1 and CYP3A4 gene polymorphisms in Chinese Hans and Chileans (Rosales et al 2012;Jiang et al 2012), and the CYP3AP1*3 allele in Chinese women were also correlated to response to atorvastatin. Thus, other loci could relate to the effects seen in this study.…”

Section: Discussionmentioning

confidence: 97%

The role of Multidrug Resistance-1 (MDR1) variants in response to atorvastatin among Jordanians

et al. 2014

The MDR1 gene encodes for P-glycoprotein (P-gp), which is an efflux transporter at the cell membrane. The P-gp has wide substrate specificity for multiple medications including the lipid lowering drug, atorvastatin. In this study, we investigated the possible association between three common MDR1 gene polymorphisms (G2677T, C3435T, and C1236T), and the lipid lowering effect of atorvastatin among Jordanians. Lipid and lipoproteins were measured in blood samples collected from patients (n = 201) at baseline and during atorvastatin treatment. MDR1 polymorphisms were genotyped using polymerase chain reaction-restriction fragment length polymorphism. Both the TT genotype of G2677T and the TT genotype of the C3435T polymorphisms were associated with lower levels of low-density lipoproteins after atorvastatin treatment. However, the effects of atorvastatin on the levels of total cholesterol, triglycerides, and high-density lipoprotein, were not correlated with any of the genotypes in both polymorphisms. Finally, the C1236T polymorphism was not associated with the lipid lowering effect of atorvastatin. In conclusion, the MDR1 gene polymorphisms G2677T, and C3435T, but not C1236T were associated with the lipid lowering effect of atorvastatin among Jordanians.