Pharmacogenomics Study Of UGT1A6 Gene In Different Chinese Ethnic Groups

The human UDP-glucuronosyltransferase enzymes (UGTs) superfamily constitutes important drug metabolizing enzymes in the human. It has been estimated to be involved in the metabolism of many endogenous substrates and extragenous substrates, as well as in the metabolism of about 30% of clinically prescribed drugs. The members of the UGT superfamily demonstrate 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 (such as schizophrenia, cardiovascular disease, hypertension and cancer etc). An understanding of the genetic variation will improve the ability to predict a patient's drug responses, adjust the therapeutic regimen and decrease the adverse drug reactions.With the availability of complete human genomic sequence, 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 UGT1A6 alleles (haplotypes) have been publicized and mainly come from Caucasians and African-Americans as well as Japanese and Korean. There are little known about Chinese population and different Chinese racial groups.We carried out the first systematic screening of polymorphisms of the gene in an SNP analysis involving 1074 Chinese subjects from three ethnic groups, namely Han, Dong and She, using direct sequencing. A total of 16 SNPs were detected including 9 known and 7 novel SNPs. The novel SNPs were 73G>A (V25I), 89T>G (L30R), 222A>C, 657C>A, 773A>T (D258V), 1040A>G (N347S) and 1467C>T. In addition, we detected, for the first time in the Chinese population, SNPs 105C>T, 308C>A (S103X), 627G>T, IVS2+15T>C and 1088C>T (P363L). Linkage disequilibrium and haplotype analysis was also made. Strong linkage disequilibrium was observed among 19T>G, 315A>G, 541A>G and 552A>C. There were seven haplotypes whose frequencies were more than 0.01 in one or more of the three ethnic groups. The analysis provided a comprehensive picture of the kinds and frequencies of SNPs of UGT1A6 in the population, including 541A>G and 552A>C which are associated with low enzyme activity.These studies may have an important significance for the understanding of genotype and phenotype relationships of UGT1A6. The further analysis of UGT1A6 SNPs will reveal the differences in individuals and ethnic groups. The applications of such information are particularly relevant for pharmacogenomics, in which knowledge of SNPs in UGT1A6 genes may lead to individualized drug dosing, decreased the adverse drug response and improved therapeutics. Moreover, an understanding of the genetic variation that exists in various populations will aid in tailoring health care to different populations, especially Chinese minority ethnic groups.