Frequency of common CYP3A5 gene variants in healthy Polish newborn infants

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

“…Significant interethnic differences in the distribution of allele frequencies rs776746*G and rs776746*A was observed (Table 3) [6,21,25,36,[44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63]. The rs776746*G allele is common in European popula tions and less common in Asian populations, and a significantly lower number of cases was observed in black populations.…”

Section: Resultsmentioning

confidence: 99%

CYP2D6, CYP3A5, and CYP3A4 gene polymorphisms in Russian, Tatar, and Bashkir populations

et al. 2015

The allele and genotype frequency distribution at polymorphic loci rs3892097 (184G>A) of CYP2D6 gene, rs776746 (6986A>G) of the CYP3A5 gene and rs2740574 (-392A>G) of the CYP3A4 gene in Russians, Tatars, and Bashkirs was examined. Samples were taken from residents of Bashkortostan Republic (1240 men and women aged from 20 to 109 years and consisted of 443 Russians, 517 Tatars, and 280 Bash kirs). Allele identification was conducted using PCR RFLP or PCR with TaqMan probes. The "nonfunc tional" allele rs3892097*A of the CYP2D6 gene was detected in populations of Russians, Tatars, and Bashkirs in 17.2, 9.5, and 7.1% cases, respectively.The rs776746*G allele of the CYP3A5 gene encoding the CYP3A5 isoenzyme with decreased activity was revealed with a frequency of 94.6% in populations of Russians, 94.3% in the Tatar population, and 91.5% in the Bashkir population. The share of the minor allele rs2740574*G of the CYP3A4 was 4.0% in populations of Russians, 0.5% in the Tatar population, and 0.9% in the Bashkir pop ulation. It has been previously shown that the rs3892097*A, rs776746*G, and rs2740574*G allele frequencies vary significantly in different world populations. Since allele variants of CYP2D6, CYP3A5, and CYP3A4 genes can play essential role in interindividual and in interethnic differences in the metabolism of many therapeutic agents, the obtained results could be used in the prognosis of pharmacotherapy efficacy in populations of Russians, Tatars, and Bashkirs.

“…The CYP3A4*22 genotype was determined with 10 ng genomic of DNA in an allelic discrimination reaction performed with TaqMan ® (Applied Biosystems, Foster City, CA, USA) genotyping assays (C_59013445_10) using a 7300 Real Time PCR System ® (Applied Biosystems). The CYP3A5*3 genotype was determined according to a previously published method (Adler et al, 2009). …”

Section: Methodsmentioning

confidence: 99%

The <i>CYP3A4</i> intron 6 C>T polymorphism (<i>CYP3A4*22</i>) is associated with reduced CYP3A4 protein level and function in human liver microsomes

et al. 2013

Effects of the CYP3A4 intron 6 C>T (CYP3A4*22) polymorphism, which has recently been reported to have a critical role in vivo, were investigated by measuring CYP3A4 protein expression levels and CYP3A4-dependent drug oxidation activities in individual human liver microsomes in vitro. Prior to protein analysis, analysis of DNA samples indicated that 36 Caucasian subjects were genotyped as CYP3A4*1/*1 and five subjects were CYP3A4*1/*22, with a CYP3A4*22 allelic frequency of 6.1%. No CYP3A4*22 alleles were found in the Japanese samples (106 alleles). Individual differences in CYP2D6-dependent dextromethorphan O-demethylation activities in liver microsomes from Caucasians were not affected by either the CYP3A4*1/*22 or CYP3A5*1/*3 genotype. Liver microsomes genotyped as CYP3A4*1/*22 (n=4) showed significantly lower CYP3A-dependent dextromethorphan N-demethylation, midazolam 1′-hydroxylation, and testosterone 6β-hydroxylation activities, as well as lower expression levels of CYP3A protein (28% of control), compared with those of the CYP3A4*1/*1 group (n=19). The other polymorphism, CYP3A5*1/*3, did not show these differences (n=4). The CYP3A4*22 polymorphism was associated with reduced CYP3A4 protein expression levels and resulted in decreased CYP3A4-dependent activities in human livers. The present results suggest an important role of low expression of CYP3A4 protein associated with the CYP3A4*22 allele in the individual differences in drug clearance.