获得性再生障碍性贫血患者Shelterin、TERT基因表达及其与中医证型关系的研究
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摘要
目的：对获得性再生障碍性贫血患者外周血单个核细胞的端粒保护蛋白复合体shelterin及端粒酶逆转录酶TERT的表达水平进行研究，探讨它们之间及与获得性再障的关系，并研究它们与再障辨证分型之间的关系，以期为再障的发生发展、治疗及预后提供更准确的依据。
方法：收集60例符合纳入标准的获得性再障患者（其中慢性再障52例，急性再障8例；中医辨证分型的急劳髓枯型8例，肾阳虚型18例，肾阴虚型19例，肾阴阳两虚型15例）的外周血单个核细胞，提取RNA，并记录其血常规情况。另收集20例健康人外周血单个核细胞标本做正常对照。采用实时荧光定量聚合酶链反应（real-time quantitative polymerase chain reaction, RT-qPCR）检测端粒保护蛋白复合体shelterin的六个蛋白TRF1、TRF2、RAP1、TIN2、TPP1和POT1及端粒酶逆转录酶（TERT）在获得性再障和正常对照组外周血单个核细胞中的mRNA表达情况，分析其与外周血白细胞以及相互之间的表达相关性。
结果：1、获得性再障患者TRF1、RAP1mRNA表达水平较正常对照组明显升高，均有显著性差异（TRF1，P＜0.01；RAP1，P＜0.05）；TRF2、POT1、TIN2mRNA表达水平较正常对照组明显降低（POT1、TRF2，P＜0.01；TIN2，P＜0.05）。2、急性再障、慢性再障患者TRF1、RAP1mRNA表达情况均较正常对照组明显升高（P＜0.05）；急性再障、慢性再障患者TIN2、POT1mRNA表达情况均较正常对照组明显降低（P＜0.05）；急性再障患者TRF2mRNA表达情况较正常对照组显著降低（P＜0.05）；急性再障患者TIN2mRNA表达情况较慢性再障患者明显降低（P=0.039，P＜0.05）。3、中医辨证分型的肾阴虚型、急痨髓枯型患者TRF1、RAP1mRNA的表达水平较正常对照组明显升高（P＜0.05）；肾阴虚型TRF2、TIN2、POT1mRNA的表达水平较正常对照组明显降低（TRF2、POT1，P＜0.05；TIN2，P＜0.01）；肾阴阳两虚型和急痨髓枯型获得性再障患者TIN2、POT1mRNA的表达水平均较正常对照组明显降低（P＜0.05）。4、中医各证型间，肾阴虚型、肾阴阳两虚型、急痨髓枯型患者TIN2mRNA表达水平均较肾阳虚型明显降低（肾阴虚型P=0.027，P＜0.05；肾阴阳两虚型P=0.016，P＜0.05；急痨髓枯型P=0.002，P＜0.01）；肾阴虚型患者TPP1mRNA表达水平较肾阳虚型患者明显降低（P=0.041，P＜0.05）；肾阳虚型患者TERTmRNA表达水平较肾阴虚型、肾阴阳两虚型、急痨髓枯型患者明显升高（P＜0.05）。5、TIN2mRNA表达水平与白细胞及淋巴细胞有明显相关性；POT1mRNA表达水平与年龄有明显相关性；TERT mRNA表达水平与红细胞及血红蛋白有明显相关性。6、TERT与TRF1、TPP1、POT1mRNA表达水平之间存在相关性；TRF2与TPP1、POT1、RAP1、TIN2mRNA表达水平之间存在相关性；TPP1与TERT、TRF2、POT1、RAP1mRNA表达水平之间存在相关性；TIN2与TRF1、TRF2、POT1mRNA表达水平之间存在相关性。
结论：1、端粒保护蛋白shelterin组分的TRF1、TRF2、TIN2、POT1、RAP1以及端粒酶逆转录酶（TERT）水平的改变可能在获得性再障的发病中起一定作用；并且TIN2、POT1、TERT可能与获得性再障的发病关系更密切。2、TRF1、RAP1在肾阴虚型最高，在肾阳虚型最低；TRF2、TIN2、POT1、TPP1在在肾阴虚型中最低，肾阳虚型中最高。提示，与肾阳虚型患者相比，肾阴虚型患者可能存在着更为严重的病变，端粒损耗程度和造血细胞凋亡可能更严重。
Objectives: To study the mRNA expression levels of telomere protection proteincomplex shelterin and telomerase reverse transcriptase (TERT) in acquired aplastic anemiapatients’ peripheral blood mononuclear cells, explore the relationship between them andacquired aplastic anemia,as well as different TCM syndromes, in order to provide moreaccurate basis of the occurrence,development, treatment and prognosis of aplastic anemia.
Methods: Collected Peripheral blood mononuclear cells of60cases with AcquiredAplastic Anemia accordanced with the inclusion criteriamet (in which8cases were acuteaplstic anemia and52cases were chronic aplstic anemia;8cases were acute tuberculosismarrow drying thermy,18cases were deficiency of kidney-yang,19cases were deficiencyof kidney-yin,15cases were deficiency of kidney-yin-and-yang), extraced RNA,andrecorded patients’ blood cell count. In addition,collected peripheral blood mononuclear cellof20normal subjects as control group.Used real-time quantitative polymerase chainreaction(RT-qPCR) to detect mRNA expression of shelterin including TRF1、TRF2、RAP1、TIN2、TPP1、POT1and TERT.Analyzed the relationship of each other,and betweenthem and leucocyte count of peripheral blood.
Results:1. The expression levels of TRF1and RAP1mRNA in patients with AcquiredAplastic Anemia were higher significantly than control group, there were significantdifferences(TRF1，P＜0.01； RAP1，P＜0.05).The expression levels of TRF2、POT1andTIN2mRNA in patients with Acquired Aplastic Anemia were lower significantly thancontrol group(POT1、TRF2，P＜0.01；TIN2，P＜0.05).
2. The expression levels of TRF1and RAP1mRNA in patients with acute aplsticanemia and chronic aplstic anemia were all higher significantly than control group(P＜ 0.05),while POT1and TIN2mRNA were all lower significantly than control group(P＜0.05). The expression levels of TRF2mRNA in patients with acute aplstic anemia werelower significantly than control group(P＜0.05). The expression levels of TIN2mRNA inpatients with acute aplstic anemia were lower significantly than chronic aplstic anemia (P＜0.05).
3. The expression levels of TRF1and RAP1mRNA in patients with deficiency ofkidney-yin and acute tuberculosis marrow drying thermy were all higher significantly thancontrol group(P＜0.05). The expression levels of TRF2、TIN2and POT1with deficiencyof kidney-yin were lower significantly than control group(TRF2、POT1，P＜0.05；TIN2，P＜0.01). The expression levels of TIN2、POT1mRNA in patients with acute tuberculosismarrow drying thermy and deficiency of kidney-yin-and-yang were all lower significantlythan control group(P＜0.05).
4. The expression levels of TIN2mRNA in patients with deficiency of kidney-yin,deficiency of kidney-yin-and-yang and acute tuberculosis marrow drying thermy werelower significantly than patients with deficiency of kidney-yang(P＜0.05). The expressionlevels of TPP1mRNA with deficiency of kidney-yin were lower significantly thandeficiency of kidney-yang (P＜0.05). The expression levels of TERT mRNA in patientswith deficiency of kidney-yang were higher significantly than patients with deficiency ofkidney-yin, deficiency of kidney-yin-and-yang and acute tuberculosis marrow dryingthermy (P＜0.05).
5. There was significant correlation between the expression levels of TIN2mRNA andleucocytes,as well as lymphocytes.There was significant correlation between theexpression levels of POT1mRNA and age. There was significant correlation between theexpression levels of TERT mRNA and red blood corpuscle,as well as hemoglobin.
6. There was significant correlation between the expression levels of TERT mRNAand TRF1、TPP1、POT1mRNA. There was significant correlation between the expressionlevels of TRF2mRNA and TPP1、POT1、RAP1、TIN2mRNA. There was significantcorrelation between the expression levels of TPP1mRNA and TERT、TRF2、POT1、RAP1mRNA. There was significant correlation between the expression levels of TIN2mRNAand TRF1、TRF2、POT1mRNA.
Conclusions:1. Changes in expression levels of TRF1、TRF2、TIN2、POT1、RAP1 and TERT probablely play a role in the pathogenesis of acquired aplastic anemia. Therewas significant correlation between the expression levels of TERT、TIN2mRNA andleucocytes,as well as lymphocytes.It suggests that TIN2、POT1and TERT is more closelyrelated to the pathogenesis of acquired aplastic anemia.
2. The expression levels of TRF1and RAP1mRNA were the highest in patients withdeficiency of kidney-yin,and the lowest in patients with deficiency of kidney-yang. Theexpression levels of TRF2、TIN2、POT1and TPP1mRNA were the highest in patients withdeficiency of kidney-yang,and the lowest in patients with deficiency of kidney-yin.Itsuggested that patients with deficiency of kidney-yin might be more serious lesions,andtelomere loss and apoptosis of hematopoietic cell might be more serious degree thandeficiency of kidney-yang.
方法：收集60例符合纳入标准的获得性再障患者（其中慢性再障52例，急性再障8例；中医辨证分型的急劳髓枯型8例，肾阳虚型18例，肾阴虚型19例，肾阴阳两虚型15例）的外周血单个核细胞，提取RNA，并记录其血常规情况。另收集20例健康人外周血单个核细胞标本做正常对照。采用实时荧光定量聚合酶链反应（real-time quantitative polymerase chain reaction, RT-qPCR）检测端粒保护蛋白复合体shelterin的六个蛋白TRF1、TRF2、RAP1、TIN2、TPP1和POT1及端粒酶逆转录酶（TERT）在获得性再障和正常对照组外周血单个核细胞中的mRNA表达情况，分析其与外周血白细胞以及相互之间的表达相关性。
结果：1、获得性再障患者TRF1、RAP1mRNA表达水平较正常对照组明显升高，均有显著性差异（TRF1，P＜0.01；RAP1，P＜0.05）；TRF2、POT1、TIN2mRNA表达水平较正常对照组明显降低（POT1、TRF2，P＜0.01；TIN2，P＜0.05）。2、急性再障、慢性再障患者TRF1、RAP1mRNA表达情况均较正常对照组明显升高（P＜0.05）；急性再障、慢性再障患者TIN2、POT1mRNA表达情况均较正常对照组明显降低（P＜0.05）；急性再障患者TRF2mRNA表达情况较正常对照组显著降低（P＜0.05）；急性再障患者TIN2mRNA表达情况较慢性再障患者明显降低（P=0.039，P＜0.05）。3、中医辨证分型的肾阴虚型、急痨髓枯型患者TRF1、RAP1mRNA的表达水平较正常对照组明显升高（P＜0.05）；肾阴虚型TRF2、TIN2、POT1mRNA的表达水平较正常对照组明显降低（TRF2、POT1，P＜0.05；TIN2，P＜0.01）；肾阴阳两虚型和急痨髓枯型获得性再障患者TIN2、POT1mRNA的表达水平均较正常对照组明显降低（P＜0.05）。4、中医各证型间，肾阴虚型、肾阴阳两虚型、急痨髓枯型患者TIN2mRNA表达水平均较肾阳虚型明显降低（肾阴虚型P=0.027，P＜0.05；肾阴阳两虚型P=0.016，P＜0.05；急痨髓枯型P=0.002，P＜0.01）；肾阴虚型患者TPP1mRNA表达水平较肾阳虚型患者明显降低（P=0.041，P＜0.05）；肾阳虚型患者TERTmRNA表达水平较肾阴虚型、肾阴阳两虚型、急痨髓枯型患者明显升高（P＜0.05）。5、TIN2mRNA表达水平与白细胞及淋巴细胞有明显相关性；POT1mRNA表达水平与年龄有明显相关性；TERT mRNA表达水平与红细胞及血红蛋白有明显相关性。6、TERT与TRF1、TPP1、POT1mRNA表达水平之间存在相关性；TRF2与TPP1、POT1、RAP1、TIN2mRNA表达水平之间存在相关性；TPP1与TERT、TRF2、POT1、RAP1mRNA表达水平之间存在相关性；TIN2与TRF1、TRF2、POT1mRNA表达水平之间存在相关性。
结论：1、端粒保护蛋白shelterin组分的TRF1、TRF2、TIN2、POT1、RAP1以及端粒酶逆转录酶（TERT）水平的改变可能在获得性再障的发病中起一定作用；并且TIN2、POT1、TERT可能与获得性再障的发病关系更密切。2、TRF1、RAP1在肾阴虚型最高，在肾阳虚型最低；TRF2、TIN2、POT1、TPP1在在肾阴虚型中最低，肾阳虚型中最高。提示，与肾阳虚型患者相比，肾阴虚型患者可能存在着更为严重的病变，端粒损耗程度和造血细胞凋亡可能更严重。
Objectives: To study the mRNA expression levels of telomere protection proteincomplex shelterin and telomerase reverse transcriptase (TERT) in acquired aplastic anemiapatients’ peripheral blood mononuclear cells, explore the relationship between them andacquired aplastic anemia,as well as different TCM syndromes, in order to provide moreaccurate basis of the occurrence,development, treatment and prognosis of aplastic anemia.
Methods: Collected Peripheral blood mononuclear cells of60cases with AcquiredAplastic Anemia accordanced with the inclusion criteriamet (in which8cases were acuteaplstic anemia and52cases were chronic aplstic anemia;8cases were acute tuberculosismarrow drying thermy,18cases were deficiency of kidney-yang,19cases were deficiencyof kidney-yin,15cases were deficiency of kidney-yin-and-yang), extraced RNA,andrecorded patients’ blood cell count. In addition,collected peripheral blood mononuclear cellof20normal subjects as control group.Used real-time quantitative polymerase chainreaction(RT-qPCR) to detect mRNA expression of shelterin including TRF1、TRF2、RAP1、TIN2、TPP1、POT1and TERT.Analyzed the relationship of each other,and betweenthem and leucocyte count of peripheral blood.
Results:1. The expression levels of TRF1and RAP1mRNA in patients with AcquiredAplastic Anemia were higher significantly than control group, there were significantdifferences(TRF1，P＜0.01； RAP1，P＜0.05).The expression levels of TRF2、POT1andTIN2mRNA in patients with Acquired Aplastic Anemia were lower significantly thancontrol group(POT1、TRF2，P＜0.01；TIN2，P＜0.05).
2. The expression levels of TRF1and RAP1mRNA in patients with acute aplsticanemia and chronic aplstic anemia were all higher significantly than control group(P＜ 0.05),while POT1and TIN2mRNA were all lower significantly than control group(P＜0.05). The expression levels of TRF2mRNA in patients with acute aplstic anemia werelower significantly than control group(P＜0.05). The expression levels of TIN2mRNA inpatients with acute aplstic anemia were lower significantly than chronic aplstic anemia (P＜0.05).
3. The expression levels of TRF1and RAP1mRNA in patients with deficiency ofkidney-yin and acute tuberculosis marrow drying thermy were all higher significantly thancontrol group(P＜0.05). The expression levels of TRF2、TIN2and POT1with deficiencyof kidney-yin were lower significantly than control group(TRF2、POT1，P＜0.05；TIN2，P＜0.01). The expression levels of TIN2、POT1mRNA in patients with acute tuberculosismarrow drying thermy and deficiency of kidney-yin-and-yang were all lower significantlythan control group(P＜0.05).
4. The expression levels of TIN2mRNA in patients with deficiency of kidney-yin,deficiency of kidney-yin-and-yang and acute tuberculosis marrow drying thermy werelower significantly than patients with deficiency of kidney-yang(P＜0.05). The expressionlevels of TPP1mRNA with deficiency of kidney-yin were lower significantly thandeficiency of kidney-yang (P＜0.05). The expression levels of TERT mRNA in patientswith deficiency of kidney-yang were higher significantly than patients with deficiency ofkidney-yin, deficiency of kidney-yin-and-yang and acute tuberculosis marrow dryingthermy (P＜0.05).
5. There was significant correlation between the expression levels of TIN2mRNA andleucocytes,as well as lymphocytes.There was significant correlation between theexpression levels of POT1mRNA and age. There was significant correlation between theexpression levels of TERT mRNA and red blood corpuscle,as well as hemoglobin.
6. There was significant correlation between the expression levels of TERT mRNAand TRF1、TPP1、POT1mRNA. There was significant correlation between the expressionlevels of TRF2mRNA and TPP1、POT1、RAP1、TIN2mRNA. There was significantcorrelation between the expression levels of TPP1mRNA and TERT、TRF2、POT1、RAP1mRNA. There was significant correlation between the expression levels of TIN2mRNAand TRF1、TRF2、POT1mRNA.
Conclusions:1. Changes in expression levels of TRF1、TRF2、TIN2、POT1、RAP1 and TERT probablely play a role in the pathogenesis of acquired aplastic anemia. Therewas significant correlation between the expression levels of TERT、TIN2mRNA andleucocytes,as well as lymphocytes.It suggests that TIN2、POT1and TERT is more closelyrelated to the pathogenesis of acquired aplastic anemia.
2. The expression levels of TRF1and RAP1mRNA were the highest in patients withdeficiency of kidney-yin,and the lowest in patients with deficiency of kidney-yang. Theexpression levels of TRF2、TIN2、POT1and TPP1mRNA were the highest in patients withdeficiency of kidney-yang,and the lowest in patients with deficiency of kidney-yin.Itsuggested that patients with deficiency of kidney-yin might be more serious lesions,andtelomere loss and apoptosis of hematopoietic cell might be more serious degree thandeficiency of kidney-yang.
引文
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