Association of cytochromes P450 3A4*22 and 3A5*3 genotypes and polymorphism with response to simvastatin in hypercholesterolemia patients

Elbatool G Elalem; Musharraf Jelani; Alaa Khedr; Aftab Ahmad; Tareef Y Alaama; Mohamed Nabeel Alaama; Huda M Al-Kreathy; Zoheir A Damanhouri

doi:10.1371/journal.pone.0260824

Association of cytochromes P450 3A422 and 3A53 genotypes and polymorphism with response to simvastatin in hypercholesterolemia patients

PLoS One. 2022 Jul 15;17(7):e0260824. doi: 10.1371/journal.pone.0260824. eCollection 2022.

Authors

Elbatool G Elalem¹, Musharraf Jelani^{2

3}, Alaa Khedr⁴, Aftab Ahmad⁵, Tareef Y Alaama⁶, Mohamed Nabeel Alaama⁶, Huda M Al-Kreathy¹, Zoheir A Damanhouri¹

Affiliations

¹ Department of Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
² Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
³ Princess Al-Jawhara Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia.
⁴ Department of Analytical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia.
⁵ Health Information Technology Department, Jeddah Community College, King Abdulaziz University, Jeddah, Saudi Arabia.
⁶ Department of Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.

Abstract

Backgrounds: Inter-individual variability in response to statin was mainly due to genetic differences. This study aimed to investigate the association of CYP3A4*22 (rs35599367), CYP3A5*3 (rs776746) single nucleotide polymorphism (SNP) with response to simvastatin in hypercholesterolemia patients conducted at King Abdulaziz University hospital (KAUH) in Jeddah, Saudi Arabia.

Patients and methods: A total of 274 participants were registered in the current study. Hypercholesterolemic patients taking simvastatin 20 mg (n = 148) and control subjects (n = 126) were tested for rs35599367 and rs776746 genotypes using Custom Taqman ® Assay Probes. Response to simvastatin in these patients was assessed by determination of low density lipoprotein (LDL-C), total cholesterol (TC) and by measuring statin plasma levels using Liquid Chromatography-Mass Spectrometry (LC-MS).

Results: None of the participants carried a homozygous CYP3A4*22 mutant genotype, while 12 (4.4%) individuals had a heterozygous genotype and 262 (95.6%) had a wild homozygous genotype. The CYP3A5*3 allele was detected in the homozygous mutant form in 16 (5.8%) individuals, while 74 (27.0%) individuals carried the heterozygous genotype and 184 (67.2%) carried the wildtype homozygous genotype. Of the patient group, 15 (11%) were classified as intermediate metabolizers (IMs) and 133 (89%) as extensive metabolizers (EMs). Plasma simvastatin concentrations for the combined CYP3A4/5 genotypes were significantly (P<0.05) higher in the IMs group than in the EMs group. TC and plasma LDL-C levels were also significantly (P<0.05) higher in IMs than in EMs.

Conclusion: The present study showed associations between CYP3A4*22 (rs35599367) and CYP3A5*3 (rs776746) SNP combination genotypes with response to statins in hypercholesterolemia. Patients who had either a mutant homozygous allele for CYP3A5*3 or mutant homozygous and heterozygous alleles for CYP3A4*22 showed increased response to lower TC and LDL-C levels.

MeSH terms

Cholesterol, LDL / genetics
Cytochrome P-450 CYP3A* / genetics
Genotype
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors* / therapeutic use
Hypercholesterolemia* / drug therapy
Hypercholesterolemia* / genetics
Polymorphism, Single Nucleotide
Simvastatin* / pharmacokinetics
Simvastatin* / therapeutic use

Substances

Cholesterol, LDL
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Simvastatin
Cytochrome P-450 CYP3A

Grants and funding

The project was funded by King Abdulaziz University (KAU), under grant number (2-287-1434-HiCi).The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.