西藏不同海拔高度世居藏族和移居人群高原适应不全的流行病学调查与分子机制研究
发布时间：2018-09-18 08:37
【摘要】：目的青藏高原是人类生存具有挑战性的环境之一,在青藏高原上生活的藏族人群适应了高原低压低氧环境而成为高原世居人群。本文将从世居藏族各个系统的高原适应情况进行流行病学调查,以及选择与藏族低氧适应相关的候选基因来探讨世居藏族高原低氧适应相关性,找出与世居藏族低氧适应相关候选基因多态位点,为高原医学研究提供理论依据。方法1.流行病学调查:在西藏不同海拔高度拉萨市(3650)、山南市(3600)、林芝市(2900)、日喀则市(4100)四个市采用偶遇调查方法,对当地世居者和移居者共2884人(总共发放4000个问卷表,其去掉无效问卷,最后获得有效问卷有2884个)进行调查,其中有1691个世居藏族和1193个移居者(汉族为主)通过自行设计的问卷调查表,以自填的方式进行流行病学调查。问卷内容包括各系统(呼吸、神经、消化系统和循环系统等)的变化情况。收集的数据进行统一录入,并采用SPSS17.0统计软件进行分析,其中计数资料采用卡方检验(卡方值进行哈迪温伯格检验)。2.候选基因分型,本课题前期通过全基因组等位基因分型(genome wide association study,GWADS)方法筛选出的与藏族低氧适应相关的候选基因钠钙交换因子(SLC8A1)、蛋白激酶C(PRKCE)、细胞色素C氧化酶合成的核编码基因(CMC2)、促血管新生蛋白因子(ANGPT4)、腺苷酸脱氨酶家族成员之一(AMPD3)、驱动蛋白超家族(KIF1B)和基因编码肾上腺素受体(ADRA1A),本课题选择了241例世居藏族和Hap MapⅢ期中北方和南方平原汉族(208例)利用Sequenom Mass Arry平台对(ADRA1A基因的rs1177946、rs6557946、rs7842829、rs1048101、rs1442341;位于SLC8A1基因上的rs4952404、rs13031392、rs2192771;PRKCE基因上的rs11898209、rs6544852、rs6756452、rs3768753、rs10205024、rs2278775、rs3820729、rs2594489、rs2594494、rs7571879;KIF1B基因上的rs10492970、rs17034615、rs17034716、rs2297881)共4个候选基因22个SNP位点利用Squenom Mass ARRAY检测平台进行扩大样本验证。所获得数据采用SPSS17.0统计软件进行分析,计量资料采用T检验,计数资料采用卡方检验,进行哈迪-温伯格平衡(Hardy-Weinberg equilibrium)检验,群体表型的比较采用单因素方差分析,用T检验计算基因型对临床表型的影响,用plink软件进行与表型的关联分析,以P0.05为差异有统计学意义。结果1.流行病学调查:本次调查获得2884个不同海拔高度的世居者和移居者,其中拉萨市世居者579人,移居者536人;女性526人,男性589人;山南市世居者250人,移居者281人;女性164人,男性367人;林芝市世居者153人,移居者206人;女性152人,男性207人;日喀则市世居者708人,移居者171人;女性472人,男性407人;调查发现世居者总的高原不适应率为34.9%,而移居者总的高原不适应率为52.9%,其世居者和移居者神经系统不适应率为37.1%和50.7%;循环系统的不适应率为23.6%和48.9%;消化系系统不适应率为36.4%和44.3%。在不同海拔高度的四个地区的世居者和移居者总的高原不适应情况调查显示,拉萨世居者和移居者总的不适应率为34.5%和48.0%;山南世居者和移居者总的不适应率为38.3%和52.3%;日喀则世居者和移居者总的不适应率为29.6%和52.2%;林芝世居者和移居者总的不适应率为55.9%和67.2%,在4个不同海拔高度的世居者和移居者各组间有统计学差异。2.表型数据分析:对241例世居藏族的临床生化表型进行统计,发现世居藏族的临床生化指标基本在正常参考值范围内,其反应心室收缩功能的心功能指标EF(射血分数%)较高与正常参考值。在世居藏族中男性是73.77±4.86%;女性是73.63±4.36%。3.候选基因的分型:4个候选基因的22个SNP位点在世居藏族和平原汉族之间进行两两比较,并进行与表型的关联分析,发现4个候选基因均在不同人群中基因型频率差异显著且最小等位基因频率具有显著相关性(P㩳0.05)。首先对4个候选基因的22个SNP位点进行基因型频率比较,发现KIF1B基因上的4个(rs10492970、rs17034615、rs17034716、rs2297881)SNP位点的基因型频率均在世居藏族和平原汉族中各组间比较均有显著差异(P㩳0.05)。SLC8A1基因上的2个(rs4952404、rs13031392)SNP位点的基因型频率在世居藏族和平原汉族中各组间比较均均有显著差异(P㩳0.05)。ADRA1A基因上的5个(rs1177946、rs6557946、rs7842829、rs1048101、rs1442341)SNP位点的基因型频率在世居藏族和平原汉族中各组间比较均有显著差异(P㩳0.05),PRKCE基因上的10个(rs11898209、rs6544852、rs6756452、rs3768753、rs10205024、rs2278775、rs3820729、rs2594489、rs2594494、rs7571879)SNP位点的基因型频率在世居藏族和平原汉族中各组间比较均有显著差异(P㩳0.05)。我们还对4个候选基因的22个SNP位点在世居藏族和平原汉族中进行频率差异性进行比较,发现KIF1B基因上的4个SNP位点;ADRA1A基因的5个SNP位点;SLC8A1基因上的2个(rs4952404、rs13031392)SNP位点;PRKCE基因上的10个SNP位点均具有显著差异性(P㩳0.05)。此外,我们发现了SLC8A1基因上rs4952404和rs13031392位点,PRKCE基因上的rs7571879、rs6756452、rs3820729和rs2278775位点,ADRA1A基因上的rs7842829位点的最小等位基因频率随着海拔升高而增大,其在安多人群中显示最小等位基因频率最大。4.数量性状关联分析我们对具有表型数据的世居藏族(241例)通过数量性状关联分析发现PRKCE基因上的rs3768753位点与每搏输出量(SV)及射血分数(EF)相关;rs2594489位点与红细胞压积(HCT)、最大肺活量(FVC)、最大呼气流量(PEF)、时间肺活量(FEV1)、血氧饱和度(Sa O2)相关;rs2594494位点与FEV1、FVC、PEF、HCT相关;rs6544852位点与Sa O2、主动脉内径(Ao)、FEV1、FVC、PEF相关;rs6756452位点与Sa O2相关。ADRA1A基因上的rs1442341位点与Sa O2相关;rs6557946、rs7842829、rs1048101位点均与A0相关;rs11779546位点与Sa O2、SV相关。KIF1B基因上的rs17034716位点与Sa O2相关;rs10492970位点与AO相关;rs17034615位点与AO相关;rs2297881位点与AO相关(P0.05)。SLC8A1基因上的rs4952404位点与Sa O2相关(P0.05)。结论1.在高原低压低氧环境下长期生活,对机体呼吸系统、神经系统、循环系统和消化系统均受到了一定程度的影响。2.世居藏族的高原适应性较移居者好,世居藏族总的高原不适应率为34.9%,而移居者总的高原不适应率为52.9%。不同海拔高度的4个地区高原不适应率没有随着海拔的升高而增加。3.进一步证明了PRKCE、SLC8A1、ADRA1A和KIF1B基因可能是藏族低氧适应相关的候选基因。4.PRKCE基因6个SNP位点(rs3768753、rs2594489、rs2594494 rs6544852、rs6756452、rs11898209)在不同海拔高度世居藏族中与表型(SV、EF、HCT、FVC、PEF、FEV1、Sa O2、Ao)有显著相关性(P0.05),因此推测PRKCE基因可能在藏族低氧适应机制中发挥着不容忽视的作用。5.SLC8A1基因rs4952404和rs13031392位点可能是藏族低氧适应相关的重要候选位点。6.ADRA1A基因rs1442341、rs7842829和rs11779546位点可能是藏族低氧适应相关的重要候选位点。7.KIF1B基因rs17034716位点可能是藏族低氧适应的重要候选位点。
[Abstract]:Objective The Qinghai-Tibet Plateau is one of the most challenging environments for human survival. The Tibetan people living on the Qinghai-Tibet Plateau have adapted to the high altitude hypobaric hypoxic environment and become the inhabitants of the world. To explore the correlation of hypoxic adaptation in Tibetan plateau and find out the candidate gene polymorphisms related to hypoxic adaptation in Tibetan plateau. Methods 1. Epidemiological investigation: Four cities of Lhasa (3650), Shannan (3600), Linzhi (2900) and Xigaze (4100) in Tibet were selected by chance. Methods A total of 2884 local residents and migrants (4000 questionnaires were sent out, and 2884 valid questionnaires were obtained after eliminating the invalid questionnaires). Among them, 1691 Tibetans and 1133 migrants (mainly Han Chinese) were investigated by self-designed questionnaires. The contents of the paper include the changes of the respiratory, nervous, digestive and circulatory systems. The collected data were input uniformly and analyzed by SPSS17.0 statistical software. The counting data were analyzed by Chi-square test (Hardy-Weinberg test for Chi-square value). 2. Candidate genotyping, which passed the whole genome allele earlier in this project. Genotyping (GWADS) method screened the candidate genes related to Tibetan hypoxic adaptation, including sodium calcium exchange factor (SLC8A1), protein kinase C (PRKCE), cytochrome C oxidase synthesis nuclear coding gene (CMC2), angiogenic protein factor (ANGPT4), adenylate deaminase family member (AMPD3), driving eggs. The white superfamily (KIF1B) and gene-encoded adrenergic receptor (ADRA1A) were selected from 241 Tibetans and 208 Han (Hap Map Phase III) in the northern and southern plains using Sequenom Mass Arry platform pairs (rs1177946, rs6557946, rs7842829, rs1048101, rs1442341; rs4952404, rs13031392, rs21) in the SLC8A1 gene. 92771; PRKCE gene on the rs11898209, rs6544852, rs6756452, rs3768753, rs10205024, rs2278775, rs3820729, rs2594489, rs2594494, rs7571879; KIF1B gene on the rs10492970, rs17034615, rs17034716, rs2297881) a total of four candidate gene 22 SNP loci using the Squenom s ARY detection platform for extended sample validation. SPSS17.0 statistical software was used to analyze the data. T-test was used to measure the data. Chi-square test was used to test the counting data. Hardy-Weinberg equilibrium test was used to test the population phenotype. One-way ANOVA was used to compare the population phenotype. T-test was used to calculate the influence of genotype on the clinical phenotype. Results: 1. Epidemiological survey: 2884 residents and immigrants at different altitudes were obtained, including 579 residents and 536 immigrants in Lhasa, 526 women and 589 men, 250 in Shannan, 281 immigrants, 164 women and 367 men, 153 in Linzhi. 206 migrants; 152 females, 207 males; 708 inhabitants, 171 migrants; 472 females, 407 males; the survey found that the total altitude maladjustment rate of the world's inhabitants was 34.9%, while the total altitude maladjustment rate of the migrants was 52.9%, and the maladjustment rates of the nervous system of the world's inhabitants and the migrants were 37.1% and 50.7%, respectively. The overall altitude maladjustment rates of the settlers and immigrants in four different altitudes were 34.5% and 48.0%, 38.3% and 52.3% respectively, and that of the Shannan settlers and immigrants was 38.3% and 52.3%, respectively. The total maladjustment rates of the inhabitants and the immigrants were 29.6% and 52.2%; the maladjustment rates of the inhabitants and the immigrants of Linzhi were 55.9% and 67.2%. There were statistical differences between the groups of the inhabitants and the immigrants at four different altitudes. 2. Phenotypic data analysis: 241 cases of the clinical biochemical phenotypes of the inhabitants were statistically analyzed. The biochemical parameters of the bed were basically within the normal reference range, and the EF (ejection fraction%) was higher and normal. Among the Tibetans living in the world, the EF (ejection fraction%) was 73.77 (+ 4.86%) in males and 73.63 (+ 4.36%) in females. The genotype frequencies of the four candidate genes were significantly different in different populations and the minimum allele frequencies were significantly correlated (P?0.05). The genotype frequencies of 22 SNP loci of the four candidate genes were compared and four of them (rs10492970, rs17034615, rs170) were found in KIF1B gene. The genotype frequencies of the two SNP loci (rs4952404, rs13031392) in the SLC8A1 gene were significantly different between the Tibetan and Han populations (P?0.05). There were significant differences in the genotype frequencies of the five ADRA1A loci (rs1177). The genotypic frequencies of the SNP loci in 946, rs6557946, rs7842829, rs1048101, rs1442341 were significantly different between Tibetans and Han Chinese (P? 0.05). The genotypic frequencies of 10 PRKCE loci (rs11898209, rs6544852, rs6756452, rs3768753, rs10205024, rs2278775, rs3820729, rs2594489, rs2594494, rs7571879) were significantly different. There were significant differences in the frequencies of 22 SNP loci of 4 candidate genes between Tibetans and Han people in the plains (P?0.05). We also compared the frequencies of 22 SNP loci of 4 candidate genes between Tibetans and Han people in the plains and found 4 SNP loci in the KIF1B gene, 5 SNP loci in the ADRA1A gene, 2 SNPs in the SLC8A1 gene (rs4952404, rs13031392). In addition, we found that the allele frequencies of rs4952404 and rs13031392 in SLC8A1, rs7571879, rs6756452, rs3820729 and rs2278775 in PRKCE, and rs7842829 in ADRA1A increased with elevation. Quantitative trait association analysis revealed that rs3768753 locus in PRKCE gene was associated with stroke output (SV) and ejection fraction (EF), rs2594489 locus with hematocrit (HCT) and maximal vital capacity (MVC) in 241 Tibetans with phenotypic data. FVC, maximum expiratory flow (PEF), time vital capacity (FEV1), blood oxygen saturation (Sa O2) were correlated; rs2594494 locus was correlated with FEV1, FVC, PEF, HCT; rs6544852 locus was correlated with Sa O2, Ao, FEV1, FVC, PEF; rs6756452 locus was correlated with Sa O2; rs6557946, rs7842829, rs1048101 locus was correlated with ADRA1A; rs6557946, rs7842829, rs1048101 locus was correlated with Sa O2; The rs17034716 locus on the KIF1B gene was associated with Sa O2; the rs10492970 locus was associated with AO; the rs17034615 locus was associated with AO; the rs2297881 locus was associated with AO (P 0.05). The rs4952404 locus on the SLC8A1 gene was associated with Sa O2 (P 0.05). Conclusion 1. The body respiratory system, nervous system, circulatory system and digestive system were all affected to a certain extent. 2. The altitude adaptability of the Tibetans living in the world was better than that of the immigrants. The altitude maladjustment rate of the Tibetans living in the world was 34.9%, while that of the immigrants was 52.9%. PRKCE, SLC8A1, ADRA1A and KIF1B may be candidate genes related to hypoxic adaptation in Tibetans. 4. Six SNP loci (rs3768753, rs2594489, rs2594494, rs6544852, rs6756452, rs11898209) of PRKCE gene were significantly correlated with phenotypes (SV, EF, HCT, FVC, PEF, FEV1, Sa O2, Ao) in Tibetans at different altitudes. Sex (P 0.05), so PRKCE gene may play an important role in Tibetan hypoxic adaptation mechanism. 5. SLC8A1 gene rs4952404 and rs13031392 loci may be important candidate loci related to Tibetan hypoxic adaptation. 6. ADRA1A gene rs1442341, rs7842829 and rs11779546 loci may be important candidate loci related to Tibetan hypoxic adaptation. The rs17034716 locus of locus.7.KIF1B may be an important candidate for hypoxic adaptation in Tibetan.
【学位授予单位】：西藏大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R594.3
本文编号：2247355
[Abstract]:Objective The Qinghai-Tibet Plateau is one of the most challenging environments for human survival. The Tibetan people living on the Qinghai-Tibet Plateau have adapted to the high altitude hypobaric hypoxic environment and become the inhabitants of the world. To explore the correlation of hypoxic adaptation in Tibetan plateau and find out the candidate gene polymorphisms related to hypoxic adaptation in Tibetan plateau. Methods 1. Epidemiological investigation: Four cities of Lhasa (3650), Shannan (3600), Linzhi (2900) and Xigaze (4100) in Tibet were selected by chance. Methods A total of 2884 local residents and migrants (4000 questionnaires were sent out, and 2884 valid questionnaires were obtained after eliminating the invalid questionnaires). Among them, 1691 Tibetans and 1133 migrants (mainly Han Chinese) were investigated by self-designed questionnaires. The contents of the paper include the changes of the respiratory, nervous, digestive and circulatory systems. The collected data were input uniformly and analyzed by SPSS17.0 statistical software. The counting data were analyzed by Chi-square test (Hardy-Weinberg test for Chi-square value). 2. Candidate genotyping, which passed the whole genome allele earlier in this project. Genotyping (GWADS) method screened the candidate genes related to Tibetan hypoxic adaptation, including sodium calcium exchange factor (SLC8A1), protein kinase C (PRKCE), cytochrome C oxidase synthesis nuclear coding gene (CMC2), angiogenic protein factor (ANGPT4), adenylate deaminase family member (AMPD3), driving eggs. The white superfamily (KIF1B) and gene-encoded adrenergic receptor (ADRA1A) were selected from 241 Tibetans and 208 Han (Hap Map Phase III) in the northern and southern plains using Sequenom Mass Arry platform pairs (rs1177946, rs6557946, rs7842829, rs1048101, rs1442341; rs4952404, rs13031392, rs21) in the SLC8A1 gene. 92771; PRKCE gene on the rs11898209, rs6544852, rs6756452, rs3768753, rs10205024, rs2278775, rs3820729, rs2594489, rs2594494, rs7571879; KIF1B gene on the rs10492970, rs17034615, rs17034716, rs2297881) a total of four candidate gene 22 SNP loci using the Squenom s ARY detection platform for extended sample validation. SPSS17.0 statistical software was used to analyze the data. T-test was used to measure the data. Chi-square test was used to test the counting data. Hardy-Weinberg equilibrium test was used to test the population phenotype. One-way ANOVA was used to compare the population phenotype. T-test was used to calculate the influence of genotype on the clinical phenotype. Results: 1. Epidemiological survey: 2884 residents and immigrants at different altitudes were obtained, including 579 residents and 536 immigrants in Lhasa, 526 women and 589 men, 250 in Shannan, 281 immigrants, 164 women and 367 men, 153 in Linzhi. 206 migrants; 152 females, 207 males; 708 inhabitants, 171 migrants; 472 females, 407 males; the survey found that the total altitude maladjustment rate of the world's inhabitants was 34.9%, while the total altitude maladjustment rate of the migrants was 52.9%, and the maladjustment rates of the nervous system of the world's inhabitants and the migrants were 37.1% and 50.7%, respectively. The overall altitude maladjustment rates of the settlers and immigrants in four different altitudes were 34.5% and 48.0%, 38.3% and 52.3% respectively, and that of the Shannan settlers and immigrants was 38.3% and 52.3%, respectively. The total maladjustment rates of the inhabitants and the immigrants were 29.6% and 52.2%; the maladjustment rates of the inhabitants and the immigrants of Linzhi were 55.9% and 67.2%. There were statistical differences between the groups of the inhabitants and the immigrants at four different altitudes. 2. Phenotypic data analysis: 241 cases of the clinical biochemical phenotypes of the inhabitants were statistically analyzed. The biochemical parameters of the bed were basically within the normal reference range, and the EF (ejection fraction%) was higher and normal. Among the Tibetans living in the world, the EF (ejection fraction%) was 73.77 (+ 4.86%) in males and 73.63 (+ 4.36%) in females. The genotype frequencies of the four candidate genes were significantly different in different populations and the minimum allele frequencies were significantly correlated (P?0.05). The genotype frequencies of 22 SNP loci of the four candidate genes were compared and four of them (rs10492970, rs17034615, rs170) were found in KIF1B gene. The genotype frequencies of the two SNP loci (rs4952404, rs13031392) in the SLC8A1 gene were significantly different between the Tibetan and Han populations (P?0.05). There were significant differences in the genotype frequencies of the five ADRA1A loci (rs1177). The genotypic frequencies of the SNP loci in 946, rs6557946, rs7842829, rs1048101, rs1442341 were significantly different between Tibetans and Han Chinese (P? 0.05). The genotypic frequencies of 10 PRKCE loci (rs11898209, rs6544852, rs6756452, rs3768753, rs10205024, rs2278775, rs3820729, rs2594489, rs2594494, rs7571879) were significantly different. There were significant differences in the frequencies of 22 SNP loci of 4 candidate genes between Tibetans and Han people in the plains (P?0.05). We also compared the frequencies of 22 SNP loci of 4 candidate genes between Tibetans and Han people in the plains and found 4 SNP loci in the KIF1B gene, 5 SNP loci in the ADRA1A gene, 2 SNPs in the SLC8A1 gene (rs4952404, rs13031392). In addition, we found that the allele frequencies of rs4952404 and rs13031392 in SLC8A1, rs7571879, rs6756452, rs3820729 and rs2278775 in PRKCE, and rs7842829 in ADRA1A increased with elevation. Quantitative trait association analysis revealed that rs3768753 locus in PRKCE gene was associated with stroke output (SV) and ejection fraction (EF), rs2594489 locus with hematocrit (HCT) and maximal vital capacity (MVC) in 241 Tibetans with phenotypic data. FVC, maximum expiratory flow (PEF), time vital capacity (FEV1), blood oxygen saturation (Sa O2) were correlated; rs2594494 locus was correlated with FEV1, FVC, PEF, HCT; rs6544852 locus was correlated with Sa O2, Ao, FEV1, FVC, PEF; rs6756452 locus was correlated with Sa O2; rs6557946, rs7842829, rs1048101 locus was correlated with ADRA1A; rs6557946, rs7842829, rs1048101 locus was correlated with Sa O2; The rs17034716 locus on the KIF1B gene was associated with Sa O2; the rs10492970 locus was associated with AO; the rs17034615 locus was associated with AO; the rs2297881 locus was associated with AO (P 0.05). The rs4952404 locus on the SLC8A1 gene was associated with Sa O2 (P 0.05). Conclusion 1. The body respiratory system, nervous system, circulatory system and digestive system were all affected to a certain extent. 2. The altitude adaptability of the Tibetans living in the world was better than that of the immigrants. The altitude maladjustment rate of the Tibetans living in the world was 34.9%, while that of the immigrants was 52.9%. PRKCE, SLC8A1, ADRA1A and KIF1B may be candidate genes related to hypoxic adaptation in Tibetans. 4. Six SNP loci (rs3768753, rs2594489, rs2594494, rs6544852, rs6756452, rs11898209) of PRKCE gene were significantly correlated with phenotypes (SV, EF, HCT, FVC, PEF, FEV1, Sa O2, Ao) in Tibetans at different altitudes. Sex (P 0.05), so PRKCE gene may play an important role in Tibetan hypoxic adaptation mechanism. 5. SLC8A1 gene rs4952404 and rs13031392 loci may be important candidate loci related to Tibetan hypoxic adaptation. 6. ADRA1A gene rs1442341, rs7842829 and rs11779546 loci may be important candidate loci related to Tibetan hypoxic adaptation. The rs17034716 locus of locus.7.KIF1B may be an important candidate for hypoxic adaptation in Tibetan.
【学位授予单位】：西藏大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R594.3
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