Genetic Polymorphism Analysis Of CYP2C9in Chinese Han And Tibetan Populations And UGT1A9,1A7,1A1in Chinese Tibetan Population

Drug efficacy and safety are important research goals of the current development of medicine. The major task of pharmacogenetics is to invest the relationship between related genotypes and drug response. Genetic polymorphisms of the drug metabolizing genes are the common cause of differences in enzyme activity which related metabolism of the same substrate, and have inter-individual, interracial differences. Therefore, studying of drug metabolism gene polymorphisms in specific ethnic group is significantly helpful to evaluate drug efficacy and develop the personalized medicine. In the present study, we mainly analyze the genetic polymorphism of CYP2C9, UGT1A9,1A7and1A1in Chinese Tibetan population.Cytochrome P450and UDP-glucuronosyl transferases (UGTs), detoxicating and eliminating various endogenous and exogenous compounds (most were drug), represent the important phase â…  and â…¡ metabolizing enzymes, respectively. CYP2C9, an important member of P450, metabolize a wide range of approximately10%of commonly clinical important drugs including S-warfarin, phenytoin, tolbutamide, fluoxetine and so on. CYP2C9is highly polymorphic, and these polymorphisms are the most important reasons that cause inter-individual, interracial differences in CYP2C9activity and metabolism of the same drug. CYP2C9*2and*3, decreasing the enzyme activity, are common alleles of CYP2C9. CYP2C9*3is the most common allele and none CYP2C9*2in Chinese Han population up to now. UGT1A9,1A7and1A1, important phase â…¡ metabolizing enzymes, influence the efficacy of diverse range of clinical important drugs such as irinotecan (a main therapeutic drug for the treatment of metastatic colorectal cancer patients). There were large inter-individual, interracial differences in UGT1A9,1A7and1A1activity, and influencing the metabolism of drugs. The polymorphisms of UGT1A9,1A7and1A1are the most important reasons that cause activity variability and many of them have been reported. It has been found that the common alleles UGT1A9*1b,1A7*3and1A1*28have relation with the efficacy of metabolism of SN-38(the active antitumor metabolite of the irinotecan). The ones who carry homozygote of UGT1A1*28are facility to get Gilbert syndrome. Therefore, studying of genetic polymorphism of CYP2C9, UGT1A9,1A7and1A1is clinically helpful to evaluate drug safety and efficacy.China is a multi-ethnic and large population nation, including56ethnic groups and Han population is the most population group (91.59%). Tibetan population is a major minority ethnic group. There are differences of diet, culture and life between the two populations. We presumed that there might be different genetic information of some important drug metabolizing genes in different populations. To date, many studies have been performed on CYP2C9, UGT1A9,1A7and1A, however, most of them are mainly come from Caucasians or African-Americans. A comprehensive search for genetic polymorphisms of CYP2C9, UGT1A9,1A7and1A1in Chinese Tibetan population and comparison of genetic polymorphism pattern of CYP2C9between Chinese Han and Tibetan populations have rarely been conducted. In the present study, by directly sequencing, we systematically screened and studied the polymorphisms of the functional region of CYP2C9in100Chinese Tibetan subjects (Qinghai province) and100Chinese Han subjects (Yulin city in Shaanxi province), respectively, and UGT1A9,1A7and IA in100Chinese Tibetan subjects.The mainly results as follows:(1)20variants were detected in the functional region of CYP2C9from100Chinese Han subjects and100Tibetan subjects, CYP2C9*3was the main functional allele in the two populations, and CYP2C9*11allele was only found in Chinese Tibetan population;(2) Analyzing by Haploview software, the results show that there were different polymorphism pattern, allele frequencies, genotype frequencies, LD blocks, dominate haplotype structures and htSNPs in CYP2C9between the two populations;(3)36variants, including eight novel variants, were identified in the functional regions of UGT1A9,1A7and1A1from Chinese Tibetan population;(4) there were four, five, six alleles and seven, eight, nine genotypes in UGT1A9,1A7and1A1genes from Chinese Tibetan population, respectively;(5) For LD analysis between variants of UGT1A9,1A7and1A1, two LD blocks (blockl and block2) were calculated, and eight common haplotypes account for blockl and three common haplotypes account for block2, respectively, in Chinese Tibetan population. The htSNPs were selected based on haplotype measure. This study first systematically and comprehensively studied and fully analyzed the genetic polymorphisms of CYP2C9, UGT1A9,1A7and1A1in Chinese Tibetan population. The determined genetic information of them might help building the databases of their allele and genotype frequencies and serve as a baseline for larger studies on determining metabolic phenotypes of them substrate drugs, and also provide important data for pharmcogenetic research and the advance of personalized medicine in Chinese Tibetan population.