髓过氧化物酶基因影响房颤发生分子遗传机制研究

发布时间：2018-06-19 06:40

本文选题：房颤 + 炎症　；参考：《华中科技大学》2015年博士论文

【摘要】：房颤是一种以快速而不规则激动为特征的心律失常,心房速率常达到350-600bpm。无论是在普通人群还是经历了心脏外科手术的患者中,房颤都是最为常见一种心律失常。流行病学研究数据显示,在欧裔人群中房颤的总发病率达1%,中国人群中总发病率约0.77%,而在80岁以上人群中则高达8%。更为严重的是,房颤会显著增加脑卒中(5倍)和心衰(3倍)的发生风险,也使得心源性猝死发生率增高2.14-3.26倍。因此,房颤已经严重影响人类健康。已有研究发现,炎症反应(inflammatory)在房颤疾病的起始和维持过程中起到非常关键的作用。然而,在此过程中,炎症反应具体充当什么样的角色,到底是房颤发生的原因,还是房颤导致的结果,仍然具有争论。此外,炎性反应和炎症信号通路影响房颤的具体分子机制仍不明确。髓过氧化物酶(Myeloperoxidase. MPO)是一种含铁血红素,由白细胞生成,其作用是在过氧化氢的作用下发生反应生成次氯酸(HOC1),次氯酸在细胞内的主要作用是调控基质金属蛋白酶(matrix metalloproteinases, MMP)活性,这一通路已发现与心房结构性重构关联紧密。动物模型研究中发现,与野生型小鼠相比,经血管经张素Ⅱ处理的MPO敲除鼠会引起白细胞激活,心房组织中MPO的催化产物3-氯酪氨酸减少,降低MMP活性,进而表现为心房肌纤维化程度大大减弱。经右心房电生理刺激后,MPO基因敲除鼠可极大程度避免电刺激引发的房颤。而当MPO基因重新导入后这种情况会被逆转。此外,相关研究也发现,房颤患者血浆MPO浓度与非房颤对照相比明显升高,右心房组织中MPO大量沉积。尽管如此,MPO基因与房颤的关联,到目前为止还没有在大规模人群中得到验证,缺乏最关键可信的遗传学证据。为探索MPO基因是否在遗传学上与房颤的发生关联,在本课题中,我们在GeneID基因库中选取了两个单独的中国汉族人群房颤病例-对照样本群体,然后选取了一个MPO基因启动子或表达调控区域内,与MPO基因表达量显著相关的转录调控型单核苷酸多态性(SNP)位点rs2243828作为我们研究的目标。同时,这一SNP与MPO血浆含量显著相关。在两个独立群体中进行了基因分型,并进行了关联性研究。结果显示,在第一个发现群体(694房颤患者和710房颤对照)中,rs2243828不同基因型在病人和对照中存在显著差异,rs2243828的G等位对于房颤的发生具有显著地保护性作用(观测P-obs=7.65×10-3,矫正后P-adj=6.25×10-3,矫正后OR为0.77)。在另一个独立的复制性群体中(1,106房颤患者和1,501对照),这一结果得到了可靠的复制,rs2243828同样发现与房颤显著相关(观测P-obs=7.28×10-5,矫正后P-adj=9.88×10-5,OR为0.75)。以上结果充分显示,MPO基因启动子区域SNPrs2243828与中国人群房颤发生风险显著相关。 Rs2243828位于MPO基因启动子区域,在177例健康人群中,我们研究了Rs2243828是否影响血清中MPO含量,结果显示,G等位携带者血清平均MPO含量约为A等位携带者的50%(P=1.16x10-4)。此外,通过分层分析还发现,Rs2243828在患有高血压的亚群体中具有更强的效应,提示其在影响房颤的过程中,可能与高血压存在相互作用。通过以上研究,我们首次发现炎症通路中的重要基因MPO启动子区域SNPRs2243828与中国汉族人群房颤风险显著关联,同时还发现其影响房颤的分子机制可能是通过影响基因的表达和血清中MPO含量来实现的。我们的研究提示炎症反应在房颤的发生过程中起到了非常关键的作用,提示炎症反应有可能成为房颤预防、诊断以及治疗的新的靶点。
[Abstract]:Atrial fibrillation is a kind of arrhythmia characterized by rapid and irregular excitement. Atrial fibrillation is often the most common arrhythmia in both the general population and patients undergoing cardiac surgery. Epidemiological data show that the total incidence of atrial fibrillation in European people is up to 1%, Chinese people are 1%. The total incidence of the group was about 0.77%, while the higher 8%. was more serious in people over 80 years of age. Atrial fibrillation could significantly increase the risk of stroke (5 times) and heart failure (3 times), and also increased the incidence of sudden cardiac death by 2.14-3.26 times. Therefore, atrial fibrillation has seriously affected human health.
It has been found that the inflammatory response (inflammatory) plays a crucial role in the initiation and maintenance of atrial fibrillation. However, in this process, what is the specific role of the inflammatory response, whether it is the cause of atrial fibrillation, or the results of atrial fibrillation, is still controversial. In addition, inflammatory responses and inflammatory signaling pathways are still in dispute. The specific molecular mechanism that affects atrial fibrillation is still unclear. Myeloperoxidase. MPO is a kind of hemoglobin containing erythropoietin, which is produced by white blood cells, and its action is to produce hypochloric acid (HOC1) under the action of hydrogen peroxide. The main function of hypochlorite in cell is to regulate matrix metalloproteinase (matrix metalloproteinases, MM). P) activity, this pathway has been found to be closely associated with structural remodeling in the atrium. In animal model studies, the MPO knockout mice treated by Zhang Su, compared with wild type mice, can cause leukocyte activation, and the catalytic product of MPO in the atrium is reduced in 3- chlortyrosine, reducing MMP activity, and thus showing a large degree of fibrosis in the atrium. MPO gene knockout rats can greatly avoid atrial fibrillation induced by electrical stimulation after electrophysiological stimulation of the right atrium. And this situation will be reversed when the MPO gene is re introduced. In addition, the related study also found that the plasma MPO concentration in patients with atrial fibrillation is significantly higher than that of non atrial fibrillation, and the MPO in the right atrium is heavily deposited. The association between MPO gene and atrial fibrillation has not been verified in large population so far, and lacks the most reliable and reliable genetic evidence.
In order to find out whether the MPO gene is genetically associated with atrial fibrillation, in this subject, we selected two individual Chinese Han Chinese people with atrial fibrillation case control samples in the GeneID gene pool, and then selected a MPO gene promoter or a transcriptional regulatory form that is significantly related to the expression of MPO gene in the regulatory region. Nucleotide polymorphism (SNP) site rs2243828 was the target of our study. At the same time, this SNP was significantly associated with MPO plasma levels. Genotyping was conducted in two independent populations and associated studies. The results showed that in the first found group (694 patients with atrial fibrillation and 710 AF controls), the different genotype of rs2243828 was in the patient and in the patients. There were significant differences in the control. The G allele of rs2243828 had a significant protective effect on the occurrence of atrial fibrillation (P-obs=7.65 x 10-3, corrected P-adj=6.25 x 10-3, and OR 0.77 after correction). In another independent replicative group (1106 patients with atrial fibrillation and 1501 controls), this result was reliably replicated, and rs2243828 was also found. There was a significant correlation with atrial fibrillation (P-obs=7.28 x 10-5, corrected P-adj=9.88 x 10-5, OR 0.75). The above results fully showed that SNPrs2243828 in the promoter region of the MPO gene was significantly associated with the risk of atrial fibrillation in the Chinese population.
Rs2243828 was located in the MPO gene promoter region. In 177 healthy people, we studied whether Rs2243828 affected MPO content in the serum. The results showed that the average serum MPO content of G allele carriers was about 50% (P=1.16x10-4) of A allele carriers. Furthermore, the stratification analysis also found that Rs2243828 was more in subpopulations with hypertension. The strong effect suggests that it may interact with hypertension in the process of affecting atrial fibrillation.
For the first time, we found that the important gene MPO promoter region SNPRs2243828 in the inflammatory pathway is significantly associated with the risk of atrial fibrillation in Chinese Han population, and the molecular mechanism that affects atrial fibrillation may be realized by affecting the expression of genes and the content of MPO in the serum. Our study suggests that the inflammatory response is in the room. The development of tremor plays a key role, suggesting that inflammation may become a new target for prevention, diagnosis and treatment of atrial fibrillation.
【学位授予单位】：华中科技大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R541.75

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