原发高血压人群外周血细胞不同基因表达的基因芯片分析
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摘要
背景
近年来高血压病发病率快速增长,并威胁到公众健康。根据最近的报道显示到2000年,全球有972,000,000人收到这类疾病的困扰,并且这个数字预计在2025年将升到15.6亿。原发性高血压被认为是复杂的、多因子影响的并具有多基因的特性的,而其的基因多效性正式生物医学领域方面的一个挑战。
原发性高血压的基因检查应用了两种重要的技术：连锁分析以及候补基因的探查。但这些传统的技术同一时间只能测定1个或少数几个基因,有一定的局限性。然而,随着技术发展,应用基因芯片的检测使得同一时间定量分析数以千计的基因表达成为可能。
方法
我们假设应用基因芯片分析可以通过外周血基因表达的不同将原发高血压患者同血压正常的患者进行区分。故对9个高血压病患者及9个正常人进行外周血标本的采集,同时对其一般状况及生化检查指标进行记录。为了达到检测的目的,我们将总RNA从外周血细胞中进行分离。RNA通过逆转录、标记并通过基因芯片(斯坦福大学,加州,美国)对基因表达进行分析。
为了确认芯片信息,10个特异表达的基因通过定量逆转录PCR选择出6个(CD36分子,溶解物交换家族4阴离子交换体成员1 (SLC4A1),神经胶质转化因子1 (NET1), sestrin蛋白3,锌指蛋白652, peroxiredoxin蛋白6),由于其高表达而被筛选出,还有4个(亨氏影响蛋白1(HIP1),叶酸感受器3(FOLR3),内质网氨基多肽1(ERAPl),补体因子D (CFD)是由于低表达而被筛选出来的。为了使qRT-PCR的数据标准化,管家基因GAPDH同每个RNA样本一起分析。所有的反应的条件都应用推荐的方法,每个反应应用0.5的引物和1μ模板。重要的是反应经过45个循环95℃,2分钟变性,94℃,15秒的复性和延长,最后的延长部分在60℃40秒。倍性变化的计算通过每个循环的三大步骤的阈值确定,并且所有的值都和GAPDH基因的表达做校正。
观察对象的人口学统计通过应用SPSS12统计学软件包进行记录和分析。组间超敏CRP水平的差别通过T检验进行分析。基因芯片的相关数据通过芯片显著性分析软件(SAM)进行分析。为了评估错误发现率(FDR), SAM通过更换重复测量的排列。基本上,通过DNA芯片分析仪完成排列标准化和计算表达值的计算。应用基因本体论浏览器(NetAffymetrix)进行合成基因的测绘。应用t检验和软件包3.0分析不同基因的倍性变化在0.5-2之间,q值≤5%,并且FDR值为5或更少。基因分类通过分子测绘系统2.0的生物本体化和KEGG生物途径进行。
结果
1、参加者的一般临床信息。在年龄、BMI、血糖以及肌酐值在各组之间统计学无差异。我们设P<0.001为统计学有意义。超敏CRP在高血压组和正常人群组中有显著性差异。超敏CRP水平在高血压组中明显高于正常对照组,同时炎症相关基因的表达也增加。
2、通过SAM检测发现存在折叠改变(≥2 or≤0.5)且表达的q值≤5%的基因中有31个上调和18个下调。值得关注地,在不同原发性高血压患者中GO(gene ontology)功能和生物程序是不同的,存在着各自的MHCⅡ分子受体活性和免疫反应。我们通过分析发现多重内在联系途径在疾病的遗传基因缺陷中起着重要的作用。
3、选取10个基因通过实时定量PCR进行分析和确认。CD36(p.,0.000),SLC4A1 (p.,5.091e-005), NET1 (p.,3.56e-008), SESN3 (p.,1.181e-005), ZNF652 (p.,0.000), PRDX6 (p., 0.000) are up-regulated and HIPI (p.,0.000), FOLR3 (p.,0.000), ERAP1 (p.,0.004) and CFD (p., 0.006)根据它们的生物学特性选出。绝对标准值曲线由线性质粒DNA产生。这10个基因皮尔森线性相关参数(R2)大于0.99。实时定量PCR的结果和基因芯片的结果一致。
讨论：
首先,我们通过对比原发性高血压患者和正常人群研究转录谱的不同。和我们假设的一样,对高血压人群外周血进行基因微阵列分析可以对高血压人群和非高血压人群进行区分,SAM阈值鉴定出31个表达上调的和18个下调的有折叠改变的基因。这些基因和GO分类用于区分高血压人群和正常人群具有重要的生物学意义。ERAP1(内质网氨肽酶1)调控血压主要是通过对血管紧张素Ⅱ和缓激肽生成的抑制作用。CD36(血栓受体)HTN发病机制中的作用是通过内皮素1的调节作用可能会进一步改变血管平滑肌细胞的性质,从而导致高血压和动脉硬化的发生。内皮素1是基本的内源性血管收缩物质。它可以促进血管平滑肌细胞的增殖,是HTN发生的一个重要机制。虽然SLC4A1对血压调节和高血压敏感,它对于高血压的发生机制仍存在疑惑,仍需要大量的研究阐明其在高血压发生机制中的作用。
分析包括免疫反应、炎症应答,血压调节,阴离子运输,DNA依赖的转录,抗原呈递,MHCⅡ类分子的肽或多糖抗原表达,转录和运输等不同生物过程中不同基因的表达。这些生物过程都可能导致高血压的发生。我们的研究表明这归咎于多个相关的生物化学过程。重要的在于细胞粘附分子,哮喘,SLE,自身免疫性甲状腺疾病,同种异体移植,移植物抗宿主,造血干细胞,抗原呈递和表达,1型糖尿病和凝血级联反应等生物化学过程的过度表现。其中最为重要的是描述高血压和免疫系统疾病之间相互关系的免疫系统的异种路径。我们研究阐明了代谢性疾病在高血压发生过程中的作用。与造血相关的基因：CD36和HLA-DRB1被作为高血压的候补基因。完善的凝血路径在宿主抵抗中很重要。完善的系统是一个蛋白降解的级联反应作为先天免疫系统的一部分。凝血系统可以促进血块形成,防治过多出血。作为一个内源性代谢级联反应,胰舒血管激肽和激肽系统在血压调节中通过激肽,缓激肽起到重要的作用。2型缓激肽受体和血管舒张,排钠利尿,外周环境抵抗力等多个生理功能有关,均可以影响血压水平。
第二,我们通过测量同时进行微阵列分析和实时定量PCR分析的患者的高敏CRP从而比较高血压患者高敏CRP水平和炎症相关基因的表达水平。另外,我们分析微阵列数据确定是否高血压患者外周血细胞可以有区别的表达炎症相关的基因。据我们所致,高血压患者高敏CRP的水平同炎症相关基因的表达是相关联的。这一发现表明炎症和HTN相关,和其他很多研究结果一致。最近,一些研究关注内皮和血管紧张素分子在高血压发展中的作用,提出炎症和内皮损伤和RAS系统相关。然而,高血压是炎症失衡的假说仍需证明。
结论：
总之,由基因介导的分子功能和生物程序中,像MHCⅡ分子受体活性和免疫反应,最终导致原发性高血压的发生。受多重内在联系途径的影响,高血压被低外显率的危险等位基因所调控,同时和其他几个慢性疾病有关。另外,高血压同炎症有着密切的关系。我们可以预见这些发现可以为高血压的预防、诊断以及疾病控制提供一个更精准和有效的平台。
The polygenic nature of essential hypertension and its dependence on environmental factors pose a challenge for biomedical research. We hypothesized that the analysis of gene expression profiles from peripheral blood cells would distinguish patients with hypertension from normotensives. In order to test this, total RNA from peripheral blood cells was isolated. RNA was reversed-transcribed and labeled and gene expression analyzed using significance Analysis Microarrays (Stanford University, CA, USA). Briefly, Significance Analysis Microarrays (SAM) thresholding identified 31 up-regulated and 18 down-regulated genes with fold changes of≥2 or≤0.5 and q-value≤5% in expression. Statistically significantly gene ontology (GO) function and biological process differentially expressed in essential hypertension were MHC classⅡreceptor activity and immune response respectively. Biological pathway analysis identified several related pathways which are associated with immune/inflammatory responses. Quantitative Real-Time RT-PCR results were consistent with the microarray results. The levels of C-reactive protein were higher in hypertensive patients than normotensives and inflammation-related genes were increased as well. In conclusion, genes enriched for "immune/inflammatory responses" may be associated with essential hypertension. The incrimination of multiple interconnected biological pathways suggests that hypertension is modulated by low-penetrance risk alleles and is connected to several other chronic conditions. In addition, there is a correlation between systemic inflammation and hypertension. It is anticipated that these findings may provide accurate and efficient strategies for prevention, diagnosis and control of this disorder.
近年来高血压病发病率快速增长,并威胁到公众健康。根据最近的报道显示到2000年,全球有972,000,000人收到这类疾病的困扰,并且这个数字预计在2025年将升到15.6亿。原发性高血压被认为是复杂的、多因子影响的并具有多基因的特性的,而其的基因多效性正式生物医学领域方面的一个挑战。
原发性高血压的基因检查应用了两种重要的技术：连锁分析以及候补基因的探查。但这些传统的技术同一时间只能测定1个或少数几个基因,有一定的局限性。然而,随着技术发展,应用基因芯片的检测使得同一时间定量分析数以千计的基因表达成为可能。
方法
我们假设应用基因芯片分析可以通过外周血基因表达的不同将原发高血压患者同血压正常的患者进行区分。故对9个高血压病患者及9个正常人进行外周血标本的采集,同时对其一般状况及生化检查指标进行记录。为了达到检测的目的,我们将总RNA从外周血细胞中进行分离。RNA通过逆转录、标记并通过基因芯片(斯坦福大学,加州,美国)对基因表达进行分析。
为了确认芯片信息,10个特异表达的基因通过定量逆转录PCR选择出6个(CD36分子,溶解物交换家族4阴离子交换体成员1 (SLC4A1),神经胶质转化因子1 (NET1), sestrin蛋白3,锌指蛋白652, peroxiredoxin蛋白6),由于其高表达而被筛选出,还有4个(亨氏影响蛋白1(HIP1),叶酸感受器3(FOLR3),内质网氨基多肽1(ERAPl),补体因子D (CFD)是由于低表达而被筛选出来的。为了使qRT-PCR的数据标准化,管家基因GAPDH同每个RNA样本一起分析。所有的反应的条件都应用推荐的方法,每个反应应用0.5的引物和1μ模板。重要的是反应经过45个循环95℃,2分钟变性,94℃,15秒的复性和延长,最后的延长部分在60℃40秒。倍性变化的计算通过每个循环的三大步骤的阈值确定,并且所有的值都和GAPDH基因的表达做校正。
观察对象的人口学统计通过应用SPSS12统计学软件包进行记录和分析。组间超敏CRP水平的差别通过T检验进行分析。基因芯片的相关数据通过芯片显著性分析软件(SAM)进行分析。为了评估错误发现率(FDR), SAM通过更换重复测量的排列。基本上,通过DNA芯片分析仪完成排列标准化和计算表达值的计算。应用基因本体论浏览器(NetAffymetrix)进行合成基因的测绘。应用t检验和软件包3.0分析不同基因的倍性变化在0.5-2之间,q值≤5%,并且FDR值为5或更少。基因分类通过分子测绘系统2.0的生物本体化和KEGG生物途径进行。
结果
1、参加者的一般临床信息。在年龄、BMI、血糖以及肌酐值在各组之间统计学无差异。我们设P<0.001为统计学有意义。超敏CRP在高血压组和正常人群组中有显著性差异。超敏CRP水平在高血压组中明显高于正常对照组,同时炎症相关基因的表达也增加。
2、通过SAM检测发现存在折叠改变(≥2 or≤0.5)且表达的q值≤5%的基因中有31个上调和18个下调。值得关注地,在不同原发性高血压患者中GO(gene ontology)功能和生物程序是不同的,存在着各自的MHCⅡ分子受体活性和免疫反应。我们通过分析发现多重内在联系途径在疾病的遗传基因缺陷中起着重要的作用。
3、选取10个基因通过实时定量PCR进行分析和确认。CD36(p.,0.000),SLC4A1 (p.,5.091e-005), NET1 (p.,3.56e-008), SESN3 (p.,1.181e-005), ZNF652 (p.,0.000), PRDX6 (p., 0.000) are up-regulated and HIPI (p.,0.000), FOLR3 (p.,0.000), ERAP1 (p.,0.004) and CFD (p., 0.006)根据它们的生物学特性选出。绝对标准值曲线由线性质粒DNA产生。这10个基因皮尔森线性相关参数(R2)大于0.99。实时定量PCR的结果和基因芯片的结果一致。
讨论：
首先,我们通过对比原发性高血压患者和正常人群研究转录谱的不同。和我们假设的一样,对高血压人群外周血进行基因微阵列分析可以对高血压人群和非高血压人群进行区分,SAM阈值鉴定出31个表达上调的和18个下调的有折叠改变的基因。这些基因和GO分类用于区分高血压人群和正常人群具有重要的生物学意义。ERAP1(内质网氨肽酶1)调控血压主要是通过对血管紧张素Ⅱ和缓激肽生成的抑制作用。CD36(血栓受体)HTN发病机制中的作用是通过内皮素1的调节作用可能会进一步改变血管平滑肌细胞的性质,从而导致高血压和动脉硬化的发生。内皮素1是基本的内源性血管收缩物质。它可以促进血管平滑肌细胞的增殖,是HTN发生的一个重要机制。虽然SLC4A1对血压调节和高血压敏感,它对于高血压的发生机制仍存在疑惑,仍需要大量的研究阐明其在高血压发生机制中的作用。
分析包括免疫反应、炎症应答,血压调节,阴离子运输,DNA依赖的转录,抗原呈递,MHCⅡ类分子的肽或多糖抗原表达,转录和运输等不同生物过程中不同基因的表达。这些生物过程都可能导致高血压的发生。我们的研究表明这归咎于多个相关的生物化学过程。重要的在于细胞粘附分子,哮喘,SLE,自身免疫性甲状腺疾病,同种异体移植,移植物抗宿主,造血干细胞,抗原呈递和表达,1型糖尿病和凝血级联反应等生物化学过程的过度表现。其中最为重要的是描述高血压和免疫系统疾病之间相互关系的免疫系统的异种路径。我们研究阐明了代谢性疾病在高血压发生过程中的作用。与造血相关的基因：CD36和HLA-DRB1被作为高血压的候补基因。完善的凝血路径在宿主抵抗中很重要。完善的系统是一个蛋白降解的级联反应作为先天免疫系统的一部分。凝血系统可以促进血块形成,防治过多出血。作为一个内源性代谢级联反应,胰舒血管激肽和激肽系统在血压调节中通过激肽,缓激肽起到重要的作用。2型缓激肽受体和血管舒张,排钠利尿,外周环境抵抗力等多个生理功能有关,均可以影响血压水平。
第二,我们通过测量同时进行微阵列分析和实时定量PCR分析的患者的高敏CRP从而比较高血压患者高敏CRP水平和炎症相关基因的表达水平。另外,我们分析微阵列数据确定是否高血压患者外周血细胞可以有区别的表达炎症相关的基因。据我们所致,高血压患者高敏CRP的水平同炎症相关基因的表达是相关联的。这一发现表明炎症和HTN相关,和其他很多研究结果一致。最近,一些研究关注内皮和血管紧张素分子在高血压发展中的作用,提出炎症和内皮损伤和RAS系统相关。然而,高血压是炎症失衡的假说仍需证明。
结论：
总之,由基因介导的分子功能和生物程序中,像MHCⅡ分子受体活性和免疫反应,最终导致原发性高血压的发生。受多重内在联系途径的影响,高血压被低外显率的危险等位基因所调控,同时和其他几个慢性疾病有关。另外,高血压同炎症有着密切的关系。我们可以预见这些发现可以为高血压的预防、诊断以及疾病控制提供一个更精准和有效的平台。
The polygenic nature of essential hypertension and its dependence on environmental factors pose a challenge for biomedical research. We hypothesized that the analysis of gene expression profiles from peripheral blood cells would distinguish patients with hypertension from normotensives. In order to test this, total RNA from peripheral blood cells was isolated. RNA was reversed-transcribed and labeled and gene expression analyzed using significance Analysis Microarrays (Stanford University, CA, USA). Briefly, Significance Analysis Microarrays (SAM) thresholding identified 31 up-regulated and 18 down-regulated genes with fold changes of≥2 or≤0.5 and q-value≤5% in expression. Statistically significantly gene ontology (GO) function and biological process differentially expressed in essential hypertension were MHC classⅡreceptor activity and immune response respectively. Biological pathway analysis identified several related pathways which are associated with immune/inflammatory responses. Quantitative Real-Time RT-PCR results were consistent with the microarray results. The levels of C-reactive protein were higher in hypertensive patients than normotensives and inflammation-related genes were increased as well. In conclusion, genes enriched for "immune/inflammatory responses" may be associated with essential hypertension. The incrimination of multiple interconnected biological pathways suggests that hypertension is modulated by low-penetrance risk alleles and is connected to several other chronic conditions. In addition, there is a correlation between systemic inflammation and hypertension. It is anticipated that these findings may provide accurate and efficient strategies for prevention, diagnosis and control of this disorder.
引文
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