Studies Of Genetics And Pharmacogenomics In Schizophrenia

Cytochrome P450 3A (CYP3A) subfamily constitutes 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 over 50% of clinically prescribed drugs. The members of the CYP3A subfamily 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 CYP3A alleles (haplotypes) have been publicized and mainly come from Caucasians or African-Americans. There are little about Chinese population and different Chinese racial groups. First, single nucleotide polymorphism (SNP) analyses of the CYP3A4, CYP3A5 and CYP3A7 gene was carried out on three groups of healthy Chinese subjects consisting of Han, She and Dong using direct sequencing. This is the first report comparing the frequencies and haplotypes of CYP3A4, CYP3A5 and CYP3A7 allelic variants in a large scale study of Chinese Han, She and Dong subjects. Significant differences were observed in the distribution of frequencies (p<0.01) and haplotypes (p<0.01) of CYP3A SNPs among the Han, She and Dong groups.Then, systematic screening for polymorphisms in the CYP3A4 gene was carried out on 60 healthy Chinese subjects consisting of 20 Han, 30 She and 10 Dong using direct sequencing. A total of 20 SNPs were found in the CYP3A4 gene, including 11 known SNPs and 9 novel SNPs.These studies may have an important significance for the understanding of genotype and phenotype relationships of CYP3As. The further analysis of CYP3A 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 CYP 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.Schizophrenia is a serious mental disorder that affects approximately 1% of the population. However, the cause and mechanism of schizophrenia is still poorly understood. Twin, family and adoption studies have provided consistent evidence that genetic factors play a major role in the pathogenesis. It is also found that schizophrenia is not a monogenic disease, but probably a polygenic disease influenced by multiple genes with small or medium risks and by environment factors as well. Many theories have been proposed to explain the mechanism of schizophrenia , e.g. abnormality of neurobiochemistry, impediment of development.In the present study, we detected the relationship between four genes-TRAR4, GAD1, CYP3A4 and CYP3A5 and scizophrenia on the basis of linkage disequilibrium theory. We genotyped SNPs using direct sequencing with case-control or family samples.No evidence was found for TRAR4 gene association with the disease. While in the association study for GAD1 gene, significant associations were revealed in both the single site analysis and haplotype analysis. In the Chinese Han samples, the three SNPs, rs3791878,rs3791858,and rs769395 showed significance to schizophrenia, the P values were 0.0007,0.0205 and 0.0296, respectively. For CYP3A4 and CYP3A5 gene, although we found no significant differences in the individual SNPs between schizophrenic patients and control groups, we did find evidence of association haplotype CYP3A4-CYP3A5 with schizophrenia and we found the most contributor haplotype G-A (p<0.0001) to it. This result supported the potential involvement of CYP3A4 and CYP3A5 or a nearby gene in the genetic etiology of schizophrenia.Inter-individual variation of drug response and adverse effects is very common in treatment of schizophrenia using antipsychotic drugs. Many studies showed that the polymorphisms in genes encoding metabolizing enzymes, drug targets and drug transporters including drug receptors may be involved in the variation of drug response. CYP3A4 has been found to be capable of metabolizing risperidone to 9-hydroxyrisperidone.Our study found that patients'serum prolactin level after risperidone treatment was significantly higher than at baseline (P<0.001). In addition, significant gender difference in the change of prolactin levels was found (P<0.001) with the increase in prolactin levels in females greater than in males. Our study confirmed that the CYP3A4*1G genotype was significantly associated with total PANSS scores on admission and the change in total PANSS scores, but not with positive and negative PANSS scores as such. We investigated the polymorphism in CYP3A4 gene to evaluate the relationship between CYP3A4 gene and the therapeutic effects of risperidone in schizophrenia.