CYP3A4*1B and CYP3A5*3 SNPs significantly impact the response of Egyptian candidates to high-intensity statin therapy to atorvastatin

Abstract

Background A single nucleotide polymorphism (SNP) is a variation in the DNA sequence that results from the alteration of a single nucleotide in the genome. Atorvastatin is used to treat hypercholesterolemia. It belongs to a class of drugs called statins, which lower elevated levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C). Research findings on the associations between the response to atorvastatin and genetic polymorphisms in CYP3A4 and CYP3A5 are inconclusive. The effects of CYP3A4*1B (rs2740574 C/T) and CYP3A5*3 (rs776746 T/C) on atorvastatin therapy have not been previously studied among Egyptians. Objective This research aimed to investigate the effects of the genetic polymorphisms CYP3A4*1B and CYP3A5*3 on atorvastatin treatment in Egyptians. Methods In this prospective cohort study, 100 subjects were genotyped for these SNPs. All participants were screened for serum lipid profiles, liver enzymes, total bilirubin (TB), and creatine kinase (CK) before and after 40 mg postatorvastatin therapy. Atorvastatin plasma levels were assessed posttreatment; atorvastatin pharmacokinetics were evaluated in five carriers of the CYP3A4*1B (T/T) and CYP3A5*3 (C/C) genotypes. Results The allele frequencies of the CYP3A4*1B and CYP3A5*3 SNPs were 86% and 83%, respectively. The CYP3A4*1B (T/T) and CYP3A5*3 (C/C) genotypes significantly improved the serum triglyceride (TG) level (P < 0.05) and elevated the TB level (P < 0.001). Atorvastatin plasma levels were greater in CYP3A4*1B (T/T) (P < 0.05) and CYP3A5*3 (C/C) (P < 0.001) genotype carriers. Both SNPs significantly affected the pharmacokinetics of atorvastatin compared with those of Egyptian volunteers and various ethnic populations. Conclusions The CYP3A4*1B and CYP3A5*3 variants were prevalent in the study participants and could impact the effectiveness and safety of atorvastatin therapy. The mutant genotype of the CYP3A4*1B SNP and the CYP3A5*3 SNP led to high atorvastatin levels. Both variants had a notable effect on the pharmacokinetics of atorvastatin among Egyptians compared with healthy Egyptians and volunteers from other ethnic populations. Overall, clinicians can learn more about the impact of both variants in response to atorvastatin. Graphical Abstract