Screening And Analysis Of CYP Genotypes Related To Drug Metabolism In Children In Beijing And Hubei

Adverse drug reactions can lead to ineffective disease treatment,injury,noncompliance with treatment and even death.Adverse drug reaction is now recognized as a global health problem that must be better addressed.Children are particularly at risk due to their changing developmental state.The incidence of adverse drug reactions in neonates in China is about 24.4%,and in children the incidence rate is about 12.9%,two to four times that of adults.Different individuals may have very different responses to the same drug because of their physical conditions and differences in their disease state.Genetic polymorphism of drug metabolism enzymes can also play a key role in determining reaction to a drug.The most important family of drug metabolizing enzymes in humans is the cytochrome P450 enzyme family(CYP450).Cytochrome P450 enzymes are involved in metabolism of the majority of commonly clinically used drugs,and individual differences in the activity of cytochrome P450 enzymes are an important factor contributing to adverse drug reactions.Much of this difference in enzymatic activity can now be attributed to genetic heterogeneity.This study selected the allele loci of clinically relevant CYP450 enzyme variants with the highest mutation frequency in Chinese population: CYP2C9**3,CYP2C19*2/*3,CYP3A4*18,CYP3A5*3.From hospitals in Beijing and Hubei,we collected 22,705 blood samples from healthy children aged 0-14 years and used fluorescent PCR to determine genotypes at the selected loci.The frequency of alleles was determined,as well as identification of regional differences in allelic frequency.In Beijing,the CYP2C9*3 allele frequency was 4.37%;CYP2C19*2 allele frequency was 30.18%,CYP2C19*3 allele frequency was 4.79%,the CYP3A4*18 allele frequency was 0.91%,and the CYP3A5*3 allele frequency was 67.38%.In Hubei,the CYP2C9*3 allele frequency was 4.09%,CYP2C19*2 allele frequency was 31.39%,the CYP2C19*3 allele frequency was 4.84%,the CYP3A4*18 allele frequency was 1.46%,and the CYP3A5*3 allele frequency was 70.53%.We found that 15 genotype combinations accounted for 93.6% and 93.3% of the variability in the Beijing and Hubei populations(N=15512,N=7193).Eight of the combinations showed significant regional differences in frequency of occurrence(P<0.05).Through this large-scale screening of CYP genotypes of children in Beijing and Hubei,we determined the frequency of clinically important CYP variants in these two regions.Given the prevalence of some of these alleles that we found in this study,especially CYP3A5*3,which results in a non-functioning form of the CYP3A5 enzyme,screening for these variants may be an important clinical tool,especially in children.Genetically guided drug and dosage choice may become an important tool for the prevention of adverse drug reaction.