移居高原汉族高原红细胞增多症流行病学调查及遗传易感机制的初步研究
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摘要
高原红细胞增多症(HAPC)是由高原低氧引起的以红细胞过度代偿性增生为主要特征的临床综合症。2004年青海国际高原医学大会提出了新的HAPC国际诊断标准，规定男性血红蛋白浓度≥21g/dl，女性血红蛋白浓度≥19g/dl可诊断为HAPC。目前还未见依据新的HAPC国诊断标准来调查移居高原汉族HAPC流行病学的文献报道。随着社会的进步，经济的发展，大量世居平原人群进入高原，移居高原人群的构成、劳动强度等已经发生了很大的变化，可能影响移居高原人群的HAPC发病率。同时，因调查地域的自然环境、海拔高度以及被调查人群的民族、年龄和职业不同等因素的影响，各地HAPC的发病率报道不一。为此，我们采用新的HAPC国际诊断标准，对不同海拔高度的移居高原汉族进行一次大样本量的HAPC流行病学调查，分析移居高原汉族HAPC发病的规律与特点，为探讨其发病机制奠定基础。
HAPC的发病具有明显的种族差异和个体易感倾向，提示HAPC的发生可能与遗传因素有关。高原环境影响机体的主要因素是缺氧，机体对高原环境的习服也是围绕着氧的摄取－运输－利用这条轴线来进行的。线粒体是机体能量代谢的中心，是组织、细胞氧利用的关键场所，机体耗能的90％以上来自于线粒体的氧化磷酸化作用。线粒体作为细胞的‘动力工厂’，在低氧引起细胞损伤和组织、细胞对低氧环境的习服过程中的作用都是至关重要的。为此，我们通过观察HAPC患者线粒体基因组DNA单核苷酸多态性的分布状况，研究HAPC发病的线粒体遗传易感机制。同时，国内外文献报道，缺氧相关核基因也与HAPC发病有密切关系。我们采用全基因组mRNA表达谱芯片观察HAPC的差异表达基因，分析其相关的信号通路，为缺氧相关核基因单核苷酸多态性与HAPC发病的相关性研究奠定基础。本课题针对上述问题进行研究。
本研究的主要内容有：①采用新的HAPC诊断标准(青海，2004)，对新疆喀喇昆仑山地区、西藏阿里地区和青藏公路沿线地区的移居高原汉族HAPC的发病情况进行调查。研究对象分为HAPC组(Hb≥21g/dl的移居高原汉族，并无其他相关疾病)和对照组(Hb＜21g/dl，健康的移居高原汉族)。采集外周静脉血，并收集受试者的人口学资料、基本生理情况、个人生活习惯和高原低氧环境暴露等相关信息，分析移居高原汉族HAPC发病的规律和特点。②采用分层卡方检验和Logistic回归统计分析HAPC患者线粒体DNA单核苷酸多态性与HAPC易感性的相关性，探讨HAPC发病的线粒体遗传易感机制。③采用全基因组mRNA表达谱芯片技术，寻找HAPC患者的差异表达基因，分析差异表达基因的功能及其参与的相关信号通路，为缺氧相关核基因单核苷酸多态性与HAPC发病的相关性研究奠定基础。
结果：
1、HAPC组的血红蛋白(Hb)浓度、年龄、收缩压、舒张压、心率和体重指数(BMI)均非常显著的高于对照组(P＜0.01)，而HAPC组的血氧饱和度则非常显著地低于对照组(P＜0.01)。
2、对于长期移居高原汉族人群而言，当血红蛋白浓度＜21g/dl时，血氧饱和度与血红蛋白浓度无显著的相关性(P＝0.158)；当血红蛋白浓度≥21g/dl时，血氧饱和度与血红蛋白浓度有非常显著的负相关性(P＜0.001)，此时，血氧饱和度随血红蛋白浓度的升高而降低。
3、移居高原的海拔高度(3700m～5380m)、移居高原人群的年龄(18岁～58岁)、高原暴露时间(3月～30年)和BMI(16.51～31.02)均与长期移居高原汉族人群的Hb浓度有非常显著的正相关性(P＜0.01)，长期移居高原汉族人群的Hb浓度和HAPC发病率随着海拔高度的升高、年龄的增大、高原暴露时间的延长和BMI的增加而增加。
4、经相关分析发现，长期移居高原汉族血浆中EPO浓度与Hb浓度有非常显著的正相关性(P＜0.01)，Hb浓度随血浆中EPO含量的增加而增加。HAPC组血浆中的促红细胞生成素(EPO)含量非常显著地高于对照组(P＜0.01)。
5、经相关分析发现，长期移居高原汉族血浆中ROS浓度与Hb浓度有非常显著的正相关性(P＜0.01)，Hb浓度随血浆中ROS含量的增加而增加。HAPC组血浆中的活性氧(ROS)含量非常显著地高于对照组(P＜0.01)。
6、HAPC组mtDNA8414T基因型的频率(19.5％)显著高于对照组(13.0％，P＝0.04，OR＝1.615，95％CI:1.02-2.555)。
7、分层分析结果显示，①在不吸烟组，携带mtDNA8414T基因型显著增加HAPC的发病风险，其OR值为2.367(95%CI:1.001-5.644)，携带mtDNA10609C基因型和mtDNA12406A基因型显著降低HAPC的发病风险，其OR值分别为0.355(95%CI:0.151-0.833)和0.292(95%CI:0.122-0.703)；②在不饮酒组，携带mtDNA10609C基因型显著降低HAPC的发病风险，其OR值为0.479(95%CI:0.254-0.906)；③在年龄≥25岁组，携带mtDNA3010A基因型显著增加HAPC的发病风险，其OR值为2.189(95%CI:1.038-4.620)，携带mtDNA12406A基因型显著降低HAPC的发病风险，其OR值为0.44(95%CI:0.196-0.987)；④在高原暴露时间＞1年组，携带mtDNA9053A基因型或mtDNA10609C基因型均显著降低HAPC的发病风险，其OR值分别为0.382(95%CI:0.152-0.961)和0.385(95%CI:0.169-0.880)。
8、采用非条件Logistic回归模型，经年龄、BMI、吸烟饮酒状况、移居高原的海拔和高原暴露时间等因素校正后，携带mtDNA10609C基因型能显著地降低长期移居高原汉族HAPC的发病风险(P=0.01，OR=0.391，95%CI:0.191-0.800)。
9、全基因组mRNA表达谱芯片结果显示，与健康对照比较后，HAPC组有9个基因的mRNA表达水平存在显著差异，其中表达上调的有5个，表达下调的有4个。其中HLA-DQB1、HLA-DQA1、HLA-DRB4和2型内质网氨肽酶(ERAP2)的主要功能是参与HLA介导的细胞免疫反应；细胞周期蛋白42(CDC42)和法尼基转移酶(FNTB)参与骨髓造血干细胞的增殖与分化。通过荧光定量PCR(qRT-PCR)证实了基因芯片结果的准确性。
结论：
1、将血红蛋白浓度≥21g/dL作为HAPC的诊断标准是合理的。
2、移居高原的海拔高度、年龄、高原暴露时间和肥胖程度是长期移居高原汉族人群患HAPC的危险因素。
3、HAPC组血浆中的ROS含量非常显著地高于对照组，并且移居高原汉族人群的Hb浓度与ROS浓度呈显著的正相关性，提示ROS与HAPC的发病有密切关系。
4、携带mtDNA3010A基因型可显著增加移居高原汉族年龄≥25岁亚组HAPC的易感性，是此亚组人群患HAPC的危险因素。
5、mtDNA8414位点多态性与移居高原汉族HAPC的易感性关联， mtDNA8414T基因型可能是移居高原汉族患HAPC的危险因素，ATP合成酶亚基6基因可能是移居高原汉族HAPC的易感基因。
6、携带mtDNA9053A基因型可显著降低移居高原时间超过1年汉族亚组HAPC的易感性，是此亚组人群患HAPC的保护因素。
7、经环境因素校正后，mtDNA10609位点多态性与移居高原汉族HAPC的易感性相关，mtDNA10609C基因型是移居高原汉族患HAPC的保护因素，ND4L基因可能是移居高原汉族HAPC的易感基因。携带mtDNA12406A基因型可显著降低移居高原汉族不吸烟亚组和年龄≥25亚组HAPC的易感性，是这二个亚组人群患HAPC的保护因素。线粒体呼吸链复合体Ⅰ可能参与了HAPC的发病。
8、CDC42和FNTB可能通过调控骨髓造血干细胞的增殖与分化，调控移居高原汉族的红系造血生成，参与了HAPC的红细胞过度增生。
9、HLA-DQB1、HLA-DQA1、HLA-DRB4和2型内质网氨肽酶(ERAP2)参与的HLA介导的细胞免疫反应与HAPC的发生有密切关系，但具体机制不明。
High altitude polycythemia (HAPC) is a clinical syndrome characterized withexcessive erythropoiesis caused by hypoxic environment in plateau. Due to different naturalenvironment and altitude in plateau, race, age and occupation of subjects, the incidence ofHAPC is reported differently from each other, also owing to application of differentdiagnostic criteria of HAPC. With social progress and economic development, a largenumber of native plain people migrate to plateau, the composition of immigrants and theirlabor intensity have changed. So, according to new international diagnostic criteria ofHAPC (2004, Qinghai. females≥19g/dl, males≥21g/dl), we perform a epidemiologicalstudy of high altitude polycythemia in Han Chinese migrated to several districts withdifferent altitude in plateau, which will lay the foundation for the pathogenesis study ofHAPC.
There are significant susceptibility tendency in HAPC within different nationality orindividual, suggesting a relationship between HAPC and heredity. Hypoxia is the mainfactor affecting normal physiological function of immigrants. Acclimatization to highaltitude is around the axis of oxygen intaking-transporting-utilizing. Mitochondrion is thecenter of cellular energy metabolism, and is a key organelle where utilization of oxygentake place. Up to90percent of ATP come from mitochondrial oxidative phosphorylation.Mitochondrion, regarded as power manufactory, act a crucial role in hypoxic cellular injuryand acclimatization to high altitude. We aim to observe distribution of mitochondrialgenomic single nucleotide polymorphisms in patients with HAPC, and study themitochondrial hereditary susceptibility mechanism of HAPC. Secondly, a number ofhypoxia related nuclear genes have been reported to correlate with HAPC. By means ofwhole genomic mRNA expression microarray technology, we detect differently expressedgenes in patients with HAPC and analyze their signaling pathway, which will profit us to study the association of hypoxia related genes polymorphisms with HAPC.
The purpose of this study include as follows:①to have a epidemiological survey ofHAPC in Han Chinese migrated to plateau, analyze regularity and character of HAPC.②tostudy the association of mitochondrial genomic polymorphisms with HAPC in Han Chinesemigrated to plateau.③to observe the differently expressed genes in patients with HAPC bymeans of microarray.
Results:
1. Compared with control group, the concentration of hemoglobin (Hb), age, systolicpressure, diastolic pressure, heart rate and body mass index (BMI) significantly increased inHAPC group (P<0.01), and the saturation of blood oxygen (SaO2) decreased obviously inHAPC group (P<0.01).
2. For Han Chinese migrated to plateau, when Hb was below21g/dL, there was nocorrelation between SaO2and Hb (P=0.158); when Hb was up to21g/dL, there wasnegative correlation between SaO2and Hb (P<0.001).
3. There were positive correlations between altitude (3700m～5380m), age (18years～58years), during of exposure to plateau (3months～30years), BMI (16.51～31.02)and incidence of HAPC (P<0.01).
4. There was positive correlations between plasma content of EPO and Hb (P<0.01).Compared with control group, the plasma content of EPO increased significantly in HAPCgroup (P<0.01).
5. There was positive correlations between plasma content of ROS and Hb (P<0.01).Compared with control group, the plasma content of ROS increased significantly in HAPCgroup (P<0.01).
6. The frequency of mtDNA8414T was significantly higher in HAPC group (vscontrol group, P＝0.04，OR＝1.615，95％CI:1.02-2.555).
7. After stratification analysis, we found that:①Compared withwild type genotype,mtDNA8414T significantly increased the risk of HAPC among the individuals with nosmoking (OR=2.367,95%CI:1.001-5.644); Compared with wild type genotype, mtDNA10609C and mtDNA12406A significantly decreased the risk of HAPC among theindividuals with no smoking (respectively, OR=0.355,95%CI:0.151-0.833and OR=0.292, 95%CI:0.122-0.703);②Compared with wild type genotype,mtDNA10609Csignificantly decreased the risk of HAPC among the individuals with no alcohol drinking(OR=0.479,95%CI:0.254-0.906);③Compared with wild type genotype, mtDNA3010Asignificantly increased the risk of HAPC among the individuals with age up to25years old(OR=2.189,95%CI:1.038-4.620); Compared with wild type genotype, mtDNA12406Asignificantly decreased the risk of HAPC among the individuals with age up to25years old(OR=0.44,95%CI:0.196-0.987);④Compared with wild type genotype, mtDNA9053Aand mtDNA10609C significantly decreased the risk of HAPC among the individuals havemigrated to plateau more than one year (respectively, OR=0.382,95%CI:0.152-0.961andOR=0.385,95%CI:0.169-0.880).
8. Multivariate Logistic regression analysis showed that mtDNA10609C significantlydecreased the risk of HAPC in Han Chinese migrated to plateau (P=0.01, OR=0.391,95%CI:0.191-0.800).
9. Nine differentially expressed genes were identified in HAPC patients usingmicroarrays: five were up-regulated and four were down-regulated. Functional analysis ofthe array data showed that cell division cycle42(CDC42) and HLA-mediated immuneresponse may be key features underlying the mechanism and development of HAPC.
Conclusion:
1. It was reasonable that we considered Hb≥21g/dl as diagnostic criteria of HAPC.
2. Altitude, age, during of exposure to plateau and obesity were risk factors of HAPCin Han Chinese migrated to plateau.
3. There were positive correlation between plasma level of ROS and Hb, suggestingthat ROS was closely related with HAPC.
4. mtDNA3010A genotype increased the risk of HAPC among the individuals withage up to25years, and was a risk factor to HAPC for this sub-group.
5. The mtDNA8414C/T polymorphism was associated with the susceptibility ofHAPC in Han migrated to plateau, and was the risk factor to HAPC. ATPase6may beHAPC susceptibility gene.
6. mtDNA9053A genotype decreased the risk of HAPC among the individuals withduring of exposure to plateau up to one year, and was a protection factor to HAPC for this sub-group.
7. Multivariate Logistic regression analysis showed that mtDNA10609C wasprotection factor to HAPC in Han migrated to plateau, ND4L may be HAPC susceptibilitygene. mtDNA12406A genotype decreased the risk of HAPC among with the individualswith no smoking or age up to25years old, and was a protection factor to HAPC for the twosub-groups. Mitochondrial respiratory chain complex Ⅰmay be involved in thepathogenesis of HAPC.
8. CDC42and FNTB may be involved in regulation of bone marrow excessivelyerythropoiesis, which induced HAPC.
9. HLA-DQB1, HLA-DQA1, HLA-DRB4and ERAP2mediated HLA-immuneresponse may be a cause of HAPC or a pathological process in development of HAPC.
HAPC的发病具有明显的种族差异和个体易感倾向，提示HAPC的发生可能与遗传因素有关。高原环境影响机体的主要因素是缺氧，机体对高原环境的习服也是围绕着氧的摄取－运输－利用这条轴线来进行的。线粒体是机体能量代谢的中心，是组织、细胞氧利用的关键场所，机体耗能的90％以上来自于线粒体的氧化磷酸化作用。线粒体作为细胞的‘动力工厂’，在低氧引起细胞损伤和组织、细胞对低氧环境的习服过程中的作用都是至关重要的。为此，我们通过观察HAPC患者线粒体基因组DNA单核苷酸多态性的分布状况，研究HAPC发病的线粒体遗传易感机制。同时，国内外文献报道，缺氧相关核基因也与HAPC发病有密切关系。我们采用全基因组mRNA表达谱芯片观察HAPC的差异表达基因，分析其相关的信号通路，为缺氧相关核基因单核苷酸多态性与HAPC发病的相关性研究奠定基础。本课题针对上述问题进行研究。
本研究的主要内容有：①采用新的HAPC诊断标准(青海，2004)，对新疆喀喇昆仑山地区、西藏阿里地区和青藏公路沿线地区的移居高原汉族HAPC的发病情况进行调查。研究对象分为HAPC组(Hb≥21g/dl的移居高原汉族，并无其他相关疾病)和对照组(Hb＜21g/dl，健康的移居高原汉族)。采集外周静脉血，并收集受试者的人口学资料、基本生理情况、个人生活习惯和高原低氧环境暴露等相关信息，分析移居高原汉族HAPC发病的规律和特点。②采用分层卡方检验和Logistic回归统计分析HAPC患者线粒体DNA单核苷酸多态性与HAPC易感性的相关性，探讨HAPC发病的线粒体遗传易感机制。③采用全基因组mRNA表达谱芯片技术，寻找HAPC患者的差异表达基因，分析差异表达基因的功能及其参与的相关信号通路，为缺氧相关核基因单核苷酸多态性与HAPC发病的相关性研究奠定基础。
结果：
1、HAPC组的血红蛋白(Hb)浓度、年龄、收缩压、舒张压、心率和体重指数(BMI)均非常显著的高于对照组(P＜0.01)，而HAPC组的血氧饱和度则非常显著地低于对照组(P＜0.01)。
2、对于长期移居高原汉族人群而言，当血红蛋白浓度＜21g/dl时，血氧饱和度与血红蛋白浓度无显著的相关性(P＝0.158)；当血红蛋白浓度≥21g/dl时，血氧饱和度与血红蛋白浓度有非常显著的负相关性(P＜0.001)，此时，血氧饱和度随血红蛋白浓度的升高而降低。
3、移居高原的海拔高度(3700m～5380m)、移居高原人群的年龄(18岁～58岁)、高原暴露时间(3月～30年)和BMI(16.51～31.02)均与长期移居高原汉族人群的Hb浓度有非常显著的正相关性(P＜0.01)，长期移居高原汉族人群的Hb浓度和HAPC发病率随着海拔高度的升高、年龄的增大、高原暴露时间的延长和BMI的增加而增加。
4、经相关分析发现，长期移居高原汉族血浆中EPO浓度与Hb浓度有非常显著的正相关性(P＜0.01)，Hb浓度随血浆中EPO含量的增加而增加。HAPC组血浆中的促红细胞生成素(EPO)含量非常显著地高于对照组(P＜0.01)。
5、经相关分析发现，长期移居高原汉族血浆中ROS浓度与Hb浓度有非常显著的正相关性(P＜0.01)，Hb浓度随血浆中ROS含量的增加而增加。HAPC组血浆中的活性氧(ROS)含量非常显著地高于对照组(P＜0.01)。
6、HAPC组mtDNA8414T基因型的频率(19.5％)显著高于对照组(13.0％，P＝0.04，OR＝1.615，95％CI:1.02-2.555)。
7、分层分析结果显示，①在不吸烟组，携带mtDNA8414T基因型显著增加HAPC的发病风险，其OR值为2.367(95%CI:1.001-5.644)，携带mtDNA10609C基因型和mtDNA12406A基因型显著降低HAPC的发病风险，其OR值分别为0.355(95%CI:0.151-0.833)和0.292(95%CI:0.122-0.703)；②在不饮酒组，携带mtDNA10609C基因型显著降低HAPC的发病风险，其OR值为0.479(95%CI:0.254-0.906)；③在年龄≥25岁组，携带mtDNA3010A基因型显著增加HAPC的发病风险，其OR值为2.189(95%CI:1.038-4.620)，携带mtDNA12406A基因型显著降低HAPC的发病风险，其OR值为0.44(95%CI:0.196-0.987)；④在高原暴露时间＞1年组，携带mtDNA9053A基因型或mtDNA10609C基因型均显著降低HAPC的发病风险，其OR值分别为0.382(95%CI:0.152-0.961)和0.385(95%CI:0.169-0.880)。
8、采用非条件Logistic回归模型，经年龄、BMI、吸烟饮酒状况、移居高原的海拔和高原暴露时间等因素校正后，携带mtDNA10609C基因型能显著地降低长期移居高原汉族HAPC的发病风险(P=0.01，OR=0.391，95%CI:0.191-0.800)。
9、全基因组mRNA表达谱芯片结果显示，与健康对照比较后，HAPC组有9个基因的mRNA表达水平存在显著差异，其中表达上调的有5个，表达下调的有4个。其中HLA-DQB1、HLA-DQA1、HLA-DRB4和2型内质网氨肽酶(ERAP2)的主要功能是参与HLA介导的细胞免疫反应；细胞周期蛋白42(CDC42)和法尼基转移酶(FNTB)参与骨髓造血干细胞的增殖与分化。通过荧光定量PCR(qRT-PCR)证实了基因芯片结果的准确性。
结论：
1、将血红蛋白浓度≥21g/dL作为HAPC的诊断标准是合理的。
2、移居高原的海拔高度、年龄、高原暴露时间和肥胖程度是长期移居高原汉族人群患HAPC的危险因素。
3、HAPC组血浆中的ROS含量非常显著地高于对照组，并且移居高原汉族人群的Hb浓度与ROS浓度呈显著的正相关性，提示ROS与HAPC的发病有密切关系。
4、携带mtDNA3010A基因型可显著增加移居高原汉族年龄≥25岁亚组HAPC的易感性，是此亚组人群患HAPC的危险因素。
5、mtDNA8414位点多态性与移居高原汉族HAPC的易感性关联， mtDNA8414T基因型可能是移居高原汉族患HAPC的危险因素，ATP合成酶亚基6基因可能是移居高原汉族HAPC的易感基因。
6、携带mtDNA9053A基因型可显著降低移居高原时间超过1年汉族亚组HAPC的易感性，是此亚组人群患HAPC的保护因素。
7、经环境因素校正后，mtDNA10609位点多态性与移居高原汉族HAPC的易感性相关，mtDNA10609C基因型是移居高原汉族患HAPC的保护因素，ND4L基因可能是移居高原汉族HAPC的易感基因。携带mtDNA12406A基因型可显著降低移居高原汉族不吸烟亚组和年龄≥25亚组HAPC的易感性，是这二个亚组人群患HAPC的保护因素。线粒体呼吸链复合体Ⅰ可能参与了HAPC的发病。
8、CDC42和FNTB可能通过调控骨髓造血干细胞的增殖与分化，调控移居高原汉族的红系造血生成，参与了HAPC的红细胞过度增生。
9、HLA-DQB1、HLA-DQA1、HLA-DRB4和2型内质网氨肽酶(ERAP2)参与的HLA介导的细胞免疫反应与HAPC的发生有密切关系，但具体机制不明。
High altitude polycythemia (HAPC) is a clinical syndrome characterized withexcessive erythropoiesis caused by hypoxic environment in plateau. Due to different naturalenvironment and altitude in plateau, race, age and occupation of subjects, the incidence ofHAPC is reported differently from each other, also owing to application of differentdiagnostic criteria of HAPC. With social progress and economic development, a largenumber of native plain people migrate to plateau, the composition of immigrants and theirlabor intensity have changed. So, according to new international diagnostic criteria ofHAPC (2004, Qinghai. females≥19g/dl, males≥21g/dl), we perform a epidemiologicalstudy of high altitude polycythemia in Han Chinese migrated to several districts withdifferent altitude in plateau, which will lay the foundation for the pathogenesis study ofHAPC.
There are significant susceptibility tendency in HAPC within different nationality orindividual, suggesting a relationship between HAPC and heredity. Hypoxia is the mainfactor affecting normal physiological function of immigrants. Acclimatization to highaltitude is around the axis of oxygen intaking-transporting-utilizing. Mitochondrion is thecenter of cellular energy metabolism, and is a key organelle where utilization of oxygentake place. Up to90percent of ATP come from mitochondrial oxidative phosphorylation.Mitochondrion, regarded as power manufactory, act a crucial role in hypoxic cellular injuryand acclimatization to high altitude. We aim to observe distribution of mitochondrialgenomic single nucleotide polymorphisms in patients with HAPC, and study themitochondrial hereditary susceptibility mechanism of HAPC. Secondly, a number ofhypoxia related nuclear genes have been reported to correlate with HAPC. By means ofwhole genomic mRNA expression microarray technology, we detect differently expressedgenes in patients with HAPC and analyze their signaling pathway, which will profit us to study the association of hypoxia related genes polymorphisms with HAPC.
The purpose of this study include as follows:①to have a epidemiological survey ofHAPC in Han Chinese migrated to plateau, analyze regularity and character of HAPC.②tostudy the association of mitochondrial genomic polymorphisms with HAPC in Han Chinesemigrated to plateau.③to observe the differently expressed genes in patients with HAPC bymeans of microarray.
Results:
1. Compared with control group, the concentration of hemoglobin (Hb), age, systolicpressure, diastolic pressure, heart rate and body mass index (BMI) significantly increased inHAPC group (P<0.01), and the saturation of blood oxygen (SaO2) decreased obviously inHAPC group (P<0.01).
2. For Han Chinese migrated to plateau, when Hb was below21g/dL, there was nocorrelation between SaO2and Hb (P=0.158); when Hb was up to21g/dL, there wasnegative correlation between SaO2and Hb (P<0.001).
3. There were positive correlations between altitude (3700m～5380m), age (18years～58years), during of exposure to plateau (3months～30years), BMI (16.51～31.02)and incidence of HAPC (P<0.01).
4. There was positive correlations between plasma content of EPO and Hb (P<0.01).Compared with control group, the plasma content of EPO increased significantly in HAPCgroup (P<0.01).
5. There was positive correlations between plasma content of ROS and Hb (P<0.01).Compared with control group, the plasma content of ROS increased significantly in HAPCgroup (P<0.01).
6. The frequency of mtDNA8414T was significantly higher in HAPC group (vscontrol group, P＝0.04，OR＝1.615，95％CI:1.02-2.555).
7. After stratification analysis, we found that:①Compared withwild type genotype,mtDNA8414T significantly increased the risk of HAPC among the individuals with nosmoking (OR=2.367,95%CI:1.001-5.644); Compared with wild type genotype, mtDNA10609C and mtDNA12406A significantly decreased the risk of HAPC among theindividuals with no smoking (respectively, OR=0.355,95%CI:0.151-0.833and OR=0.292, 95%CI:0.122-0.703);②Compared with wild type genotype,mtDNA10609Csignificantly decreased the risk of HAPC among the individuals with no alcohol drinking(OR=0.479,95%CI:0.254-0.906);③Compared with wild type genotype, mtDNA3010Asignificantly increased the risk of HAPC among the individuals with age up to25years old(OR=2.189,95%CI:1.038-4.620); Compared with wild type genotype, mtDNA12406Asignificantly decreased the risk of HAPC among the individuals with age up to25years old(OR=0.44,95%CI:0.196-0.987);④Compared with wild type genotype, mtDNA9053Aand mtDNA10609C significantly decreased the risk of HAPC among the individuals havemigrated to plateau more than one year (respectively, OR=0.382,95%CI:0.152-0.961andOR=0.385,95%CI:0.169-0.880).
8. Multivariate Logistic regression analysis showed that mtDNA10609C significantlydecreased the risk of HAPC in Han Chinese migrated to plateau (P=0.01, OR=0.391,95%CI:0.191-0.800).
9. Nine differentially expressed genes were identified in HAPC patients usingmicroarrays: five were up-regulated and four were down-regulated. Functional analysis ofthe array data showed that cell division cycle42(CDC42) and HLA-mediated immuneresponse may be key features underlying the mechanism and development of HAPC.
Conclusion:
1. It was reasonable that we considered Hb≥21g/dl as diagnostic criteria of HAPC.
2. Altitude, age, during of exposure to plateau and obesity were risk factors of HAPCin Han Chinese migrated to plateau.
3. There were positive correlation between plasma level of ROS and Hb, suggestingthat ROS was closely related with HAPC.
4. mtDNA3010A genotype increased the risk of HAPC among the individuals withage up to25years, and was a risk factor to HAPC for this sub-group.
5. The mtDNA8414C/T polymorphism was associated with the susceptibility ofHAPC in Han migrated to plateau, and was the risk factor to HAPC. ATPase6may beHAPC susceptibility gene.
6. mtDNA9053A genotype decreased the risk of HAPC among the individuals withduring of exposure to plateau up to one year, and was a protection factor to HAPC for this sub-group.
7. Multivariate Logistic regression analysis showed that mtDNA10609C wasprotection factor to HAPC in Han migrated to plateau, ND4L may be HAPC susceptibilitygene. mtDNA12406A genotype decreased the risk of HAPC among with the individualswith no smoking or age up to25years old, and was a protection factor to HAPC for the twosub-groups. Mitochondrial respiratory chain complex Ⅰmay be involved in thepathogenesis of HAPC.
8. CDC42and FNTB may be involved in regulation of bone marrow excessivelyerythropoiesis, which induced HAPC.
9. HLA-DQB1, HLA-DQA1, HLA-DRB4and ERAP2mediated HLA-immuneresponse may be a cause of HAPC or a pathological process in development of HAPC.
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