Genetic Polymorphism Analysis Of Cytochrome P4502C19 In Chineses Han Population

Cytochrome P4502C19(CYP2C19) is an important drug metabolizing enzymes in the human. It has been estimated to be involved in the metabolism of many endogenous substrates and environmental contaminants,as well as in the metabolism of about 2% of clinically prescribed drugs. The activity of CYP2C19 enzyme demonstrates greater inter-individual and interethnic variations in humans. Genetic polymorphism is the common cause of inter-individual and interethnic differences in the metabolism of the same substrate. This polymorphism influences both drug response and disease treatment. A further understanding of the CYP2C19 genetic polymorphism will be helpful for future personalized medicine, adjust the therapeutic regimen and decrease the adverse drug reactions.With the availability of complete human genome project,more and more people has considered that the variations in genomic DNA sequence,i.e. gene polymorphisms are the most important determinants for disease susceptibility,clinical phenotype diversity and different response to pharmacotherapies and environmental factors. To date,many studies have been performed on CYP2C19, however, most of them are mainly come from Caucasians or African-Americans and examined the effects of the defective alleles CYP2C19*2 and CYP2C19*3. A comprehensive search for genetic polymorphisms of CYP2C19 gene in Chinese Han population has rarely been conducted. Therefore, it is of great significance for future personalized medicine to establish the pattern of CYP2C19 genetic polymorphisms in Chinese.The Han population is the largest ethnic group in China and is spread widely over the country. There are genetic differences between different areas. In this study, we investigate the 5'-regulatory region, all the exons and their surrounding introns of CYP2C19 gene in 400 unrelated healthy Chinese Han volunteers from four different geographical locations namely Shanghai, Xi'an, Shantou and Shenyang which is representative of the east, west, south and north of China respectively, with a sample of 100 subjects in each population. Each group of 100 subjects consisted of 50 males and 50 females between 18 and 53 years of age, with the mean year 35.83. The mainly results as follows: (1) Fourteen different CYP2C19 polymorphisms, including one novel variant (-2306G>A) in the enhancer region and a novel non-synonymous one (905C>G, T302R), were identified. Some of these polymorphisms demonstrate significant differences among populations from the four different cities, such as -889T>G, IVS3-23T>C, and 991C>T. (2) CYP2C19*15 allele was the first finding in an Asian population, with a frequency of 1.2%. (3) CYP2C19*1, the wild type allele, with a frequency 69.7%, is the most common in the Chinese Han population. The prevalent defective alleles CYP2C19*2 and CYP2C19*3 with frequencies of 24.7% and 3.3%, respectively, are much higher than those reported in American European and other Caucasian populations. (4) Haplotype analysis demonstrated that the haplotype (CATCGG) was the dominating haplotype with a frequency of 38.6%. Also, the data show that the haplotype frequencies varied significantly between the four different geographic populations, for example, the haplotypes CACTAA and CATCGA.This is the first study conducted on systematically screening the polymorphisms of the whole CYP2C19 gene in Chinese Han population with such large sample. Our study established the profile of CYP2C19 polymorphisms in the Chinese Han population. Thus, we have established the pattern of CYP2D6,CYP2C19,CYP2C9 and CYP2E1 genetic polymorphisms in Chinese. These data can serve as a baseline for larger studies on the mechanism and effects of CYP2C19 polymorphism in Asian populations. It should also facilitate further drug discovery and provide important data for the advance of personalized medicine.