Deciphering Pharmacogenomics Genetic Differentiation And Population Structure In Several Ethnic Populations In China

Previous pharmacogenomics studies have shown the key factors causing various drug efficacies should be the genetic differences of the coding genes participating in the process of drug absorption,distribution,metabolism and excretion(ADME).The differences expressed as single nucleotide polymorphisms(SNP)in individual level and population level,have laid a foundation of personalized medicine in corresponding levels.China is a multi-ethnic nation composed of 56 ethnic populations with different genetic backgrounds.So far,the pharmacogenomics studies are limited to a small number of genes and loci in major ethnics and lack systematical studies in different ethnic populations especially for Kirgiz and Miao populations.The drug metabolic enzymes and transporter chip(DMET)developed by Affymetrix contains 234 genes and 1936 loci which have been confirmed to be involved in ADME process,could be used as the unique ideal platform to investigate the pharmacogenomics differences in different populations.The current study intended to decipher the genetic differences in Han,Tibetan,Uyghur,Kazak,Kirgiz,Miao and Mongol populations from the aspects of locus,gene,haplotype,genetic structure,genetic distance,evolutionary relationship and cluster analysis based on pharmacogenomics DMET chip level for the first time,and offered suggestions on clinical medication in the seven ethnic populations.The current study also analyzed the genetic structure in the seven ethnic populations followed by a comparison of which in 11 Hap Map populations from Asia,Europe and Africa,and lays a theoretical foundation for the study of origin,migration and evolution of different populations.The main results of the current study were presented as follows:1.The 1930 DMET Loci of 434 samples in seven ethnic populations were genotyped using Affymetrix DMET chip platform.The calculation of MAF,screening of polymorphic loci,common polymorphic loci and the variable loci were carried out using bioinformatics method such as Plink software,R language,etc.A total of 918 polymorphic loci were detected among which 568 were common polymorphic loci in seven ethnic populations.Decision tree and Random forest models couldn't distinguish the seven ethnic populations according to the SNP characteristics.A total of 118 variable loci affiliated with 69 genes including three variable genes CHST3,CYP2D6 and VKORC1 with more than 5 variable loci were detected after comparison of one population with another.The overall differences among the seven ethnic populations were relatively slight;however,the random forest model could perfectly distinguish Miao from other six ethnic populations,reflecting obvious differences exist between Mao and other six ethnic populations,which were consistent with the statistical results of the variable loci number.Uyghur versus Miao comparison had maximum variable loci of 46,whereas Mongol versus other six comparisons had relatively less variable loci number with a maximum number of 17,and the variable loci number among the comparisons of Uyghur,Kazak and Kirgiz populations were relatively less with a maximum number of 2.2.The analyses of haplotype forms and the corresponding frequencies of genes with more variable loci in seven populations were made using Haploview software.The different metabolizer phenotypes and the corresponding frequencies of CYP gene in seven populations were summarized referring CYP Allele Nomenclature Database.Han and Tibetan populations,Uyghur,Kazak,Kirgiz and Mongol populations have slight differences in haplotype forms and the corresponding frequencies.Miao populations have obvious differences in haplotype forms and the corresponding frequencies with other six populations.Han,Tibetan and Miao populations have more than 50% of CYP2C19 intermediary metabolizer totally whereas Uyghur and Kazak populations have a certain portion 30% of CYP2C19 ultrarapid metabolizer.Taking medications metabolized by CYP2C19 such as clopidogrel,voriconazole,sertraline,amitriptyline,lansoprazole and clobazam,Uyghur and Kirgiz populations should decrease the dosage whereas the corresponding dosage in Han,Tibetan and Miao populations should be increased.3.The population genetics characteristics in seven populations were analyzed using Structure,Arlequin,Mega,Poptree2 and Eigensoft software.Han and Tibetan populations,Uyghur,Kazak,Kirgiz and Mongol populations have similar population genetic structures,closer genetic distances,homologous evolutionary relationships,whereas Miao populations have dissimilar population genetic structures,further genetic distances,nonhomologous evolutionary relationships with the other six populations.The seven populations could be divided into three clusters: Han and Tibetan populations,Uyghur,Kazak,Kirgiz and Mongol populations,Miao populations,which are consistent with the three language families of the seven populations.4.The population genetics characteristics in globally eighteen populations were analyzed using Structure,Arlequin,Mega,Poptree2 and Eigensoft software.Han,Tibetan,Miao,CHB,CHD and JPT populations,CEU,TSI,MEX and GIH populations,ASW,MKK,LWK and YRI populations have similar population genetic structures,closer genetic distances,homologous evolutionary relationships.The globally eighteen populations could be divided into three clusters: Han,Tibetan,Miao,CHB,CHD and JPT populations,CEU,TSI,MEX and GIH populations,ASW,MKK,LWK and YRI populations,which are consistent with three origins of the eighteen populations(yellow race,white race and black race).Uygur,Kazak,Kirgiz and Mongol population have relatively similar genetic structures and closer genetic distances with both yellow and white race populations but have a closer evolutionary relationship with the yellow race.5.The current study revealed different ethnic populations have different genetic backgrounds,laying a foundation of personalized medicines in different populations.Genes with more variable loci and loci with more differences in seven ethnic populations were searched in the clinical annotation section in the Pharm GKB database,an association was found between the polymorphisms of rs16947 in CYP2D6 and the effect of timolol in the treatment of open-angle glaucoma: carriers of “T” allele have an increased risk for bradycardia as compared to carriers of “A” allele.Since the frequencies of “T” in Han,Tibetan,Uyghur,Kazak,Kirgiz,Miao and Mongol populations are 0.2128,0.4583,0.3438,0.4271,0.4043,0.0778 and 0.3488 respectively,we recommend patients of Miao populations take timolol in the treatment of primary open-angle Glaucoma patients.For patients in Tibetan,Kazak and Kirgiz populations,we recommend a gene detection before drug selection to avoid adverse drug reactions.6.The current study revealed that DMET chip could be used for analysis of genetic structures in seven Chinese ethnics with similar genetic backgrounds but no longer limited to populations with different races,proving DMET chip could be used as a replacement of genomic gene chip for analysis of population structures and backgrounds in different populations.