CYP3A5*3A allele is associated with reduced lowering-lipid response to atorvastatin in individuals with hypercholesterolemia

Department Clinical and Toxicological Analysis, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, SP, Brazil.
Clinica Chimica Acta (Impact Factor: 2.76). 08/2008; 398(1-2):15-20. DOI: 10.1016/j.cca.2008.07.032
Source: PubMed

ABSTRACT The cytochrome P450 isoenzyme 3A5 (CYP3A5) has an important role on biotransformation of xenobiotics. CYP3A5 SNPs have been associated with variations on enzyme activity that can modify the metabolism of several drugs.
In order to evaluate the influence of CYP3A5 variants on response to lowering-cholesterol drugs, 139 individuals with hypercholesterolemia were selected. After a wash-out period of 4 weeks, individuals were treated with atorvastatin (10 mg/day/4 weeks). Genomic DNA was extracted by a salting-out procedure. CYP3A5*3C, CYP3A5*6 and CYP3A5*1D were analyzed by PCR-RFLP and DNA sequencing.
>Frequencies of the CYP3A5*3C and CYP3A5*1D alleles were lower in individuals of African descent (*3C: 47.8% and *1D: 55.2%) than in non-Africans (*3C: 84.9% and *1D 84.8%, p<0.01). Non-Africans carrying *3A allele (*3C and *1D combined alleles) had lower total and LDL-cholesterol response to atorvastatin than non-*3A allele carriers (p<0.05).
CYP3A5*3A allele is associated with reduced cholesterol-lowering response to atorvastatin in non-African individuals.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background A previous study reported that the myosin regulatory light chain interacting protein (MYLIP) might serve as a novel therapeutic class for treating dyslipidemia. It contributes to variations in the levels of circulating low-density lipoprotein cholesterol (LDL-C), promoting the degradation of LDL–LDLR, thus limiting absorption. The effect of genetic variation in the MYLIP gene in a disease scenario characterized by mutations in the LDLR gene has not been previously evaluated. Objective The aim of this study was to assess the effect of the p.N342S variant on the response to lipid-lowering therapy in Brazilian patients with heterozygous familial hypercholesterolemia (FH). Patients and methods A total of 156 patients with heterozygous FH were followed up for 12 months and received lipid-lowering therapy (different doses of atorvastatin with the addition of ezetimibe in over half the patients of each genotype group). Cholesterol data were assessed, and analysis of the MYLIP rs9370867 (p.N342S) genotypes was carried out by melting curve analysis. Results Baseline total cholesterol and baseline LDL-C levels were not different between genotypes. After 1 year of treatment, LDL-C responses (expressed as mg/dl and as %) were significantly different among genotypes (AA: −79±68 and −39±27, GA: −60±79 and −27±32, and GG: −30±83 and −15±38; P=0.02 and 0.005, respectively). In addition, FH patients carrying the AA genotype were more likely to achieve LDL-C levels of less than 130 mg/dl after 1 year of treatment (75.0%) compared with patients with the GG and GA genotypes (34.5 and 34.8%, respectively; P=0.001). Conclusion Our study indicates that MYLIP p.N342S might be a pharmacogenetic marker for lipid-lowering therapy in patients with FH.
    Pharmacogenetics and Genomics 08/2014; 24(11). DOI:10.1097/FPC.0000000000000089 · 3.45 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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.
    The Open Cardiovascular Medicine Journal 02/2014; 8(1):12-7. DOI:10.2174/1874192401408010012