| Objective: The Naxi population living in the trans-plateau area of the Qinghai-Tibet Plateau developed physiological adaptations to the low-oxygen environment of the plateau.In this paper,the correlation between single nucleotide polymorphisms(SNPs)and hemoglobin(Hb)and altitude of Endothelial PAS domain protein 1(EPAS1)was studied to explore the molecular mechanism of adaptation of Naxi population to highland hypoxia environment.Methods: In this study,256 Naxi patients from 8 villages in Lijiang City,Yunnan Province were selected as the study subjects,including 93 cases with elevated hemoglobin and 163 cases with non-elevated hemoglobin.At the same time,the molecular biology technology of the SNaPshot technology platform developed by ABI was used to detect the genotypes of five SNP sites(rs4953354,rs12619696,rs13419896,rs13419896,rs75984373,rs1868092)of the sample population,and the correlation between polymorphisms and hemoglobin and altitude was statistically analyzed.Results:(1)There were genetic polymorphisms in the EPSA1 gene rs4953354,rs12619696,rs13419896,rs75984373 and rs1868092 in the hemoglobin elevated group and the non-elevated group;(2)Population genetics Hardy Weinberg(HWE)test was carried out for EPAS1 gene polymorphism in Hb non high group and high group,as well as between high and low middle altitude groups.P>0.05 indicates that it conforms to population genetics law;(3)Through univariate analysis of Hb elevation exposure factors,it was found that the polymorphisms of altitude,sex,rs126119696 and rs1868092 had an effect on the rate of hemoglobin elevation(P<0.05);(4)Polymorphisms of the rs12619696 locus of EPSA1 gene were associated with the risk of Hb elevation,and A allele,AG genotype,AA genotype,and dominant model could increase the risk of Hb elevation(Avs.G:OR=1.600,95%CI:1.109～2.329,P=0.012;AGvs.GG:OR=2.654,95%CI:1.065-6.619,P=0.036;AAvs.GG:OR=1.791,95%CI:1.122-2.859,P=0.015;DOMINANT Model: OR=2.801,95% CI:1.227-6.396,P=0.014);Polymorphisms at the rs1868092 locus of EPSA1 gene were associated with the risk of Hb elevation,and A allele,AG genotype,AA genotype,and dominant model reduced the risk of Hb elevation(A vs.G:OR=0.407,95% CI: 0.262-0.628,P<0.001;AG vs.GG:OR=0.288,95%CI:0.142-0.583,P=0.001;AA vs.GG: OR= 0.475,95% CI:0.222-0.992,P=0.041;dominant model: OR=0.283,95% CI: 0.145-0.555,P<0.001);(5)The genotype,allele and dominant pattern of rs12619696 and rs1868092 were associated with the risk of Hb increase,and the Hb(145.7±18.5g/L)of the people carrying the rs12619696 GG genotype was lower than that of the AG genotype Hb(151.4±17.3g/L)and the Hb(153.1±18.9g/L)of the people carrying the AA genotype.There was a statistically significant difference(P<0.05),and when rs12619696 GG genotype was dominant,the GG genotype Hb(145.7±18.5g/L)was also lower than that of AG+AA genotype Hb(152.1±17.9g/L)(P<0.05).The Hb(155.0±18.1g/L)of the people carrying the rs1868092 GG genotype was higher than that of the population with AG genotype Hb(146.6±17.3g/L)and the Hb(144.7±18.2g/L)of the population with the AA genotype(P<0.05),and when the rs1868092 GG genotype was dominant,the Hb(155.0±18.1g/L)of the population carrying the GG genotype was also higher than that of AG+ There were statistical differences in Hb(146.4±17.4g/L)in the AA genotype population(P<0.05);(6)The results of haplotype analysis showed that there were three haplotypes possible,among which A-A-A-T-A was the most frequent haplotype,with frequencies of42.6% and 19.4% in the Hb non-elevated group and Hb elevated group,respectively,and A-A-A-T-A haplotype had a statistically significant decrease in Hb elevation(P<0.001);(7)The frequencies of four SNPs(rs4953354,rs12619696,rs13419896,rs1868092)of EPSA1 gene were significantly different in Tibetan and Naxi populations,with statistical significance(P<0.01),while the alleles of rs4953354,rs13419896 and rs1868092 were significantly different in Naxi and CHB.Statistically significant(P<0.01);(8)The polymorphisms of the rs1868092 locus of EPSA1 gene were related to altitude,and compared with the low to moderate altitude group,the frequency of AA homozygous mutant and A allele in the high altitude group was reduced(A vs.G:OR=0.555,95%CI:0.376～0.820,P=0.003;AGvs.GG:OR=0.456,95%CI:0.271～0.765,P=0.003;AAvs.GG:OR=0.576,95%CI:0.339～0.977,P=0.034;Dominantmodel:OR=0.345,95%CI:0.149～0.800,P=0.001);(9)Compared with the rs12619696 GG genotype in the population with elevated Hb,the values of MCH and MCHC with AG/AA genotype were higher and the difference was statistically significant(P<0.05);compared with the rs1868092 GG genotype in people with elevated Hb,the values of RBC,HCT and MCHC carrying AG/AA genotypes decreased significantly(P<0.05),while the values of PLT and SaO2 carrying AG/AA genotype were increased.The difference was statistically significant(P<0.05).Conclusions:(1)There were genetic polymorphisms in the EPSA1 gene rs4953354,rs12619696,rs13419896,rs75984373 and rs1868092 in the Naxi population;(2)The frequency of mutant genotypes in the nas1 gene rs12619696 in the Naxi population was significantly higher than that in the Hb elevated group than in the Hb non-elevated group,and the hemoglobin concentration in the homozygous mutation of rs12619696 was also higher than that in the wild type.The frequency of mutant genotypes at the rs1868092 locus was significantly lower than that in the Hb elevated group than in the Hb non-elevated group,and the hemoglobin concentration in the homozygous mutation of rs1868092 was also lower than that in the wild type.(3)Haplotype A-A-A-T-A(rs4953354-rs12619696-rs13419896-rs75984373-rs1868092)can reduce the level of Hb elevation;(4)There were obvious differences between the allele frequencies of rs4953354,rs12619696,rs13419896 and rs1868092 in the Naxi population,and there were obvious differences between rs4953354,rs13419896,rs1868092 alleles frequency and CHB.(5)The polymorphism of the rs1868092 site of EPSA1 gene was related to altitude,and the frequency of its mutant A allele affected the increase of Hb,which may be the reason why the Naxi people distinguished the Tibetan plateau from adapting to high hemoglobin;(6)The rs12619696 and rs1868092 polymorphisms are associated with blood routine related indicators such as RBC,HCT,PLT,SaO2,MCH,and MCHC in the Hb elevated population. |
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