Study Of Drug-response-related Markers In Schizophrenia And The Systematic Functional Characterzation Of CYP2D6 Alleles In Chinese Han Populations

Schizophrenia is a chronic and debilitating mental disorder affecting 1% of the general population.Continuous long-term treatment is required to maintain social functioning and prevent symptom relapse,which causes significant public health and economic burden.Antipsychotic drugs are the mainstay of treatment for schizophrenia.Currently available antipsychotic drugs achieve a certain degree of clinically effective treatment of schizophrenia in about 50% of patients,a treatment failure for schizophrenia might cause weeks of unremitted illness,potential adverse drug reactions as well as large clinical and economic costs.Risperidone,clozapine,quetiapine and chlorpromazine are the most commonly used antipsychotic drugs in China.As with all antipsychotics,there are considerable individual differences in response to the four drugs,in terms of both therapeutic effects and adverse effects.Identifying the optimal treatment for a patient is often a trial and error process that can span a long time,and response is often poor.There is a pressing need to identify more drug-response-related markers based on which an individual's response to treatment and adverse drug reaction can be predicted,thus implementing personalized medicine.Toward this end,a number of pharmacogenetic studies have been performed and several candidate markers have been identified.To date,most studies have typically focused on candidate genes,sample size is often small,which make these results could not be confirmed by diffident groups.And results are not replicated across studies or population.In the present study,in order to comprehensively discover predictors of response to these four antipsychotic drugs,a total of 77 genetic variants previously found to be associated with or potentially involved in antipsychotic drug response were selected based on a pathway approach for TaqMan genotyping in a relatively large cohort of schizophrenia subjects.We performed individual polymorphisms association analysis,association of haplotypes with drug response analysis.Also,we performed combined analysis of different markers using multi-factor-dimensionality reduction method(MDR),which lay the foundation for discovering genomic variants of higher predictive values with antipsychotics treatment response in Chinese populations.We compared the list of significant SNPs in this study with those previous reported.Our study validated most of previous associations with antipsychotics response(such as CYP2D6,CYP2C19,COMT,ABCB1,DRD3 and HTR2C).And,our study provided some new findings on the current relationships between genetic polymorphisms and antipsychotics response(such as TNIK,RELN,NOTCH4 and SLC6A2).Also,we found that a combination(haplotype rs1544325-rs5993883-rs6269-rs4818 in COMT)is associated with treatment response to the four drugs.Also,multivariate interactions analysis showed that the combination of rs6269 in COMT and rs3813929 in HTR2 C may work as a powerful predictor to improve the clinical response to antipsychotics.Therefore our study is of great significance to systematically discover antipsychotics-response related markers in Chinese Han polulation,which lay the foundation for the implementation of personalized medicine in schizophrenia.Antipsychotics is mainly metabolized by cytochrome P450 2D6(CYP2D6),and CYP2D6 is highly polymorphic.These gene polymorphisms have been proven to exhibit high individual variability in catalytic activity in response to drug dosage,and therefore affect clinical drug efficacy.Therefore it's of great importance to conduct systematic fuctional characterization in Chinese Han populations.Due to the great variation of CYP2D6 allele distribution in populations of different ethnic and geographic origins,we had carried out a systematic polymorphism analysis of the CYP2D6 gene in four different geographical Han populations in China's mainland,namely,Shanghai,Shantou,Shenyang,and Xi'an,using a sample of 100 subjects from each population.Systematic analysis of the polymorphisms of this gene in different Han subpopulations will be useful for personalized medicine in the Chinese population.In the previous systematic screening study,we had already established a database of CYP2D6 gene polymorphisms for normal Chinese Han subjects.In particularly,we had identified four novel alleles: CYP2D6*75(c.4046G>A,p.Arg441His),CYP2D6*X(c.100C>T + c.2467T>C;p.Pro34 Ser + p.Leu231Pro),CYP2D6*Y(c.100C>T + c.2851C>T;p.Pro34 Ser + p.Arg296Cys)and CYP2D6*Z(c.2467T>C + c.2851C>T;p.Leu231 Pro + p.Arg296Cys).The data of the three novel alleles has been submitted to CYP2D6 Allele Nomenclature Database.These novel alleles have not been functionally characterized to date.There have been many reports about functional analysis of CYP2D6 alleles.But most of them only reported one or several alleles,and systematic functional characterization of CYP2D6 alleles in Chinese Han populations has not been reported yet.Because the phenotypic profiles of CYP2D6 alleles in a population is of great importance to the optimization of pharmacotherapy and the design of personalized medicine.So we intend to conduct a systematic functional characterization of CYP2D6 variants in the Chinese Han populations,including the four newly found alleles(CYP2D6*75,CYP2D6*X,CYP2D6*Y,CYP2D6*Z)and two previously reported variants(CYP2D6*2 and CYP2D6*10)that have higher frequencies in the Chinese Han populations.Compared with CYP2D6 wild type,CYP2D6.X,CYP2D6.Y,CYP2D6.Z,CYP2D6.10 and CYP2D6.75 exhibited significantly lower activity at different degree.Enzymatic activity of CYP2D6.2 is normal.We analyzed these seven alleles,their amino acid substitutions and enzyme activities,found that amino acid P34 might be crucial for CYP2D6 enzyme activity and catalytic efficiency.R441 is a highly conserved site,as predicted.In conclusion,our research focused on the pharmacogenomics of schizophrenia and precision medicine in Chinese Han populations.Based on a pathway approach,we first performed an integrative study by investigating most of the genetic variants previously associated with or potentially involved in four commonly used antipsychotic drug response in about 1000 Chinese schizophrenia cases.We have identified four novel genes associated with antipsychotics response.Also,we have carried out functional characterization of four novel CYP2D6 alleles,CYP2D6.2 and CYP2D6.10 in the Chinese Han populations.The research findings have laid the foundation to identify individuals at risk for nonresponsive to therapy or toxic drug effects,leading to optimal dosing recommendations,reduced adverse drug reactions and improved drug efficacy.Our study can provide a guidance for rational medication in clinic in the future.