| Purpose Qinghai-Tibetan plateau is one of the most challenging environment of human survival,after long time adaption to the low oxygen environment,Tibetan lived in Qinghai-Tibetan plateau for generations.This study performed the epidemiological investigation on physiological hypoxia adaptation of Tibetan and selected the candidate genes and SNP sites of hypoxia adaptation of Tibetan,in order to explore the Tibetan special hypoxia adaptation mechanism and benefit for the plateau medical research.Method Epidemiological investigation of respiratory,nervous,digestive and circulatory systems,both of aboriginal Tibetan and immigration Han groups were performed in four cities at Qinghai-Tibetan plateau,including Lhasa(Altitude=3650m),Shannan(Altitude=3600m),Linzhi(Altitude=2900m),Shigates(Altitude=4100m).In all of the 4000 questionnaires,2884 were valid,including 1691 answered by aboriginal Tibetan and 1193 answered by immigration Han,before the statistic analyses with Chi square test(chi square value for Hardy Weinberg test)by SPSS 17.0 software.Our previous Genome wide association(GWADS)studies had revealed that Solute carrier family 8 member A1(SLC8A1),Protein kinase C epsilon(PRKCE),C-X9-C motif containing 2(CMC2),Angiopoietin 4(ANGPT4),Adenosine monophosphate deaminase 3(AMPD3),Kinesin family member 1B(KIF1B)and Adrenoceptor alpha 1A(ADRA1A)were selected as the candidate genes of hypoxia adaptation of Tibetan.Totally22 SNP site,including rs1177946?rs6557946?rs7842829?rs1048101?rs1442341 at ADRA1 A,rs4952404?rs13031392?rs2192771 at SLC8A1,rs11898209?rs6544852?rs6756452?rs3768753?rs10205024?rs2278775?rs3820729?rs2594489?rs2594494?rs7571879 at PRKCE,rs10492970?rs17034615?rs17034716?rs2297881 at KIF1 B,were validated in genome sequence of 241 aboriginal Tibetan and 208 North and South Han within HapMap III by Squenom MassARRAY.The results were statistically analyzed by T-test,Chi square test and Hardy-Weinberg equilibrium test.Population genetic phenotype data were analyzed by One way ANOVA,and the influence of genotype on phenotype was studied with linear regression model.Except plink software was used for the association analyses between genotype and phenotype data,all of the data were statistically analyzed by SPSS 17.0 software and with p value less than0.05 considered as statistic difference.Result Epidemiological investigation results showed that all of the2884 valid questionnaires were answered by 579 aboriginal Tibetan and536 immigration Han in Lhasa(Male=589,Female=526),250 aboriginal Tibetan and 281 immigration Han in Shannan(Male=367,Female=164),153 aboriginal Tibetan and 206 immigration Han in Linzhi(Male=207,Female=152)and 708 aboriginal Tibetan and 171 immigration Han in Shigates(Male=407,Female=472).The rates of plateau inadaptation in aboriginal Tibetan were 34.9% and 52.9% in immigration Han,in which nervous system plateau inadaptation rates were 37.1% and 50.7%,circulatory system plateau inadaptation rates were 23.6% and 48.9%,and digestive system plateau inadaptation rates were 36.4% and 44.3%,in aboriginal Tibetan and immigration Han groups respectively.Among the four cities with different altitude,the rates of plateau inadaptation were 34.5% and 48.0% in Lhasa,38.3% and 52.3% in Shannan,29.6%and 52.2% in Shigates,55.9% and 67.2% in Linzhi,in aboriginal Tibetan and immigration Han groups respectively,which showed statistically significant difference among these four cities sub-groups.The statistically analyses of the clinical phenotype data of 241 aboriginal Tibetan showed that only the ejection fraction value(EF,Ventricular systolic function)were higher than the reference range value,while EF value was 73.77±4.86% in male and 73.63±4.36% in female sub-groups.Base on the comparison analyses of the genotype frequency of 22 SNP sites in 4 candidate gene between aboriginal Tibetan and immigration Han groups and association analyses with phenotype data,we found the statistically significant difference of these 4 genes between two groups and the minimum allele frequency was significantly correlated(p <0.05),such as the SNP site of rs10492970?rs17034615?rs17034716?rs2297881at KIF1 B,rs1177946?rs6557946?rs7842829?rs1048101?rs1442341at SLC8A1,rs1177946?rs6557946?rs7842829?rs1048101?rs1442341at ADRA1 A,rs11898209?rs6544852?rs6756452?rs3768753?rs10205024?rs2278775?rs3820729?rs2594489?rs2594494?rs7571879 at PRKCE,the allele frequencies were statistically significantly different between aboriginal Tibetan and immigration Han groups(p <0.05).The association analyses of these 22 SNP site at 4 genes between aboriginal Tibetan and immigration Han groups revealed that 4 SNP sites at KIF1 B,5 SNP sites at ADRA1 A,rs4952404?rs13031392 at SLC8A1 and 10 SNP sites at PRKCE were statistically significant correlated(p<0.05)In addition,the minimum allele frequencies of rs4952404 &rs13031392 at SLC8A1,rs7571879?rs6756452?rs3820729?rs2278775at PRKCE,rs7842829 at ADRA1 A were increased with altitude and showed maximum value in Anduo sub-group in aboriginal Tibetan.The quantitative trait association analyses of genotype and phenotype data of 241 aboriginal Tibetan revealed the significant correlations(p<0.05),such as at PRKCE gene,rs3768753 was associated with stroke volume(SV)and ejection fraction(EF);rs2594489 was associated with hematokrit(HCT),maximal vital volume(L-2),maximum expiratory flow volume(dl),time vital capacity(L-1)and SaO2;rs2594494 wasassociated with L-1,L-2,dl and HCT;rs6544852 was associated with aortic dimension(Ao),L-1,L-2,dl and SaO2;rs6756452 was associated with SaO2.At ADRA1 A gene,rs1442341 was associated with SaO2;rs6557946?rs7842829?rs1048101 were associated with Ao;rs11779546was associated with SaO2 and SV.At KIF1 B gene,rs17034716 was associated with SaO2;rs10492970 ? rs17034716 and rs2297881 were associated with Ao.rs4952404 at SLC8A1 gene was associated with SaO2.Conclusion1.The hypoxia environment at Qinghai-Tibetan plateau might had the injurious effect on human respiratory,nervous,digestive and circulatory systems.2.The aboriginal Tibetan had better hypoxia adaptation in Qinghai-Tibetan plateau than immigration Han group.The rates of plateau inadaptation were 34.9% and 52.9% in aboriginal Tibetan and immigration Han group respectively,while rate of plateau inadaptation was not increased with the altitude in four cities,in which the epidemiological investigation were carried out in this study.3.This study validated the PRKCE?SLC8A1?ADRA1A and KIF1 B as the Tibetan hypoxia candidate genes.4.At PRKCE gene,6 SNP sites including rs3768753?rs2594489?rs2594494 ? rs6544852 ? rs6756452 and rs11898209 were foundsignificantly correlated(p<0.05)with SV?EF?HCT?L-2?dl?L-1?SaO2 and Ao,which might suggested the important role of PRKCE in Tibetan hypoxia adaptation.5.The SNP sites including rs4952404 and rs13031392 at SLC8A1,s1442341?rs7842829 and rs11779546 at ADRA1 A and rs17034716 at KIF1 B might play important roles in Tibetan hypoxia adaptation. |
PDF Full Text Request