Pharmacogenetic Variations Analysis Of Chinese Based On The Sequencing Data From Large Population Cohort

Background and objective:Genetic variation is an important factor which could impact on the drug efficacy.However,the profile of variations in pharmacogenes among Chinese population is still unclear.Here we will collect sequencing data from Chinese population and analyze the profile of variants in pharmacogenes and their potential impacts on the drugs’ utilization in Chinese population.Methods:The quality control and populational frequency calculation of low-depth whole genome sequencing data were performed with variant quality score recalibration(VQSR)and maximum likelihood estimation method.Then,3,538 pharmacogenes from the CPIC/DPWG guidelines,FDA website,Pharm GKB database and Drugbank database,and 2,086 marketed drugs from the National Medical Products Administration(NMPA)website,as well as the relationships between these pharmacogenes and drugs were collected and reviewed for downstream analyses.Finally,the disparity of these drugs and pharmacogenes among populations were evaluated based on an unpublished algorithm proposed by ourselves,while pharmacoeconomic benefits of pharmacogenetic tests in Chinese population were analyzed for three drugs based on the decision tree model.Results:We collected non-invasive prenatal testing(NIPT)sequencing data of 206,640 Chinese and found a total of 9,080,283 variations which are located in 3,538 pharmacogenes in Chinese population based on the NIPT sequencing data.A total number of 1,577,513 variations passed the VQSR filter,which included 331,610 novel variations and 70,202 variations in the exon regions.Then we analyzed 21 variants in 18 pharmacogenes,which are treated as clinical biomarkers in 12,639 Chinese.The consistence of these variants with the NIPT sequencing data was observed,and over 26.08% Chinese patients could modify their treatment strategies according to the results of pharmacogenetic tests.We found that although the overall mutation frequency correlation coefficient of the population in various regions of China is high,the genetic characteristics of some genetic loci are different in different regions,thus may have an impact on the drug effects among regions.Among the 70,202 variations in exon regions,we found a total number of 1,096 regional specific genetic loci in Chinese population,and found that 335 pharmacogenes are different among regions in China,which may affect the utilization of 951 drugs in different regions of China.Meanwhile,as the enzyme activity analyses indicated,the genetic loci on CYP2D6,CYP2C19 and UGT1A1 will lead to the differences of the enzyme activities of these three genes among regions.Finally,we found that there are great differences in the characteristics of pharmacogenomic landscape between Chinese population and other populations.These genetic differences may have a great impact on the utilization of nervous system drugs,antiparasitic drugs,insecticidal and anthelmintic drugs,cardiovascular drugs,gastrointestinal and metabolic drugs and respiratory drugs.In addition,it is economical to carry out the pharmacogenetic tests for warfarin,clopidogrel/ticagrelor and irinotecan in Chinese population.Conclusion: The NIPT sequencing data could be utilized for analyzing the profile of variations in pharmacogenes,and we found that there are some ethnic or regional specific variations located in the pharmacogenes of Chinese population.Although it is economic efficient to carry out pharmacogenetic tests for some drugs in Chinese population,the variations’ frequencies disparities were large between Chinese and other populations like Africans and Europeans.These disparities indicated the necessity of populational specific pharmacogenetic test agents or panels of pharmacogenes according to the profile of variations in pharmacogenes among Chinese population.