Genetic Polymorphism Analysis Of Cytochrome P4503A4(CYP3A4) In Chinese Uyghur Population

Cytochrome P450CYP3A4is the most abundant enzyme in CYP450family and it plays significant role in drug metabolizing reaction. With its content, it occupies70%of CYP450totals in the intestine, while possess30%in the liver. For its metabolizing spectrum, more than50%commonly clinically used drugs are metabolized via CYP3A4of which include150kinds of drug substrates following into38categories.CYP3A4is highly polymorphic and exhibits distinct individually and ethnically differences in drug metabolizing. More than40-fold differences in enzyme expression in the liver as well as10-20fold differences in enzyme metabolizing activities were observed. Many factors can lead to these differences like environment, pathology, food, ages, sex, and hormones, but genetic factors are considered the primary one, it is estimated that90%of the enzymatic differences were attributed to genetic factors of which Single Nucleotide Polymorphisms (SNPs) are the largest part. The differences exist not only in individuals but also between populations. It has been noticed that allele frequencies of some drug metabolizing enzymes vary strikingly in groups or subgroups which could bring about different therapeutic effect within a group or subgroup for the same drug treatment, thus it holds great theoretic value to study genetic differences in drug metabolizing genes among populations in order to realize individualized medicine and more specific drug development based on populational genetic background.This study was conducted to thoroughly and systematically screen CYP3A4polymorphisms for a sample of100individuals in Uyghur by directly sequencing the gene which includes5’regulator region, all exons, surrounding introns and3’UTR region.Contents:1. Calculate frequencies of SNPs in Uyghur population, and in search for novel ones;2. Establishment of CYP3A4alleles and genotypes and its frequency distributions in Uyghur population;3. Comparison of genetic differences between populations with reference to the published data;4. Linkage Disequilibrium and haplotype analysis among detected SNPs;5. In Silicon prediction analysis of polymorphisms in the promoter, the coding and3’UTR region of CYP3A4;Results:1. A total of21CYP3A4polymorphisms were detected in Uyghur, of which9are novel ones.2. A total of9alleles and10genotypes were established in Uyghur, and CYP3A4*8was firstly report in Chinese, with a frequency of0.5%.3. Populational comparison showed that Uyghur has its particular genetic profile, and its allele frequencies differ greatly with other populations.4. Haplotype analysis showed that polymorphisms of CYP3A4in Uyghur are weakly linked and independently inherited.5. TfsiteScan showed that-549C>G makes no impact on the regulation of transcriptional factors, but not for variants-747C>G,-667C>T and-392A>G; SIFT and PolyPhen showed high consistency that novel variant16934A>T would not have much effect, but for13908G>A and23172T>C, the results were Damaging; SpliceScanⅡ showed that20230G>A could create a competitive5’ Splicing Donor site, thus disrupts normal exonic balance which may lead to alternative mRNA splicing; miRande showed that26759G>C region was in the target region of many miRNAs, thus could possibly affect miRNA regulations of the gene.Conclusion:This is the first study conducted on systematically screening the polymorphisms of CYP3A4in Uygur population. The research data filled up the empty that it lacks of data with the minority groups. It offers data reference and theory supporting for drug use safety and drug development of Uygur people, and also provides basis for futher widely and deeply CYP3A4phenotypical research and pharmacogenomics studies.