本文選題：房顫 + 炎癥��； 參考：《華中科技大學(xué)》2015年博士論文

【摘要】：房顫是一種以快速而不規(guī)則激動(dòng)為特征的心律失常,心房速率常達(dá)到350-600bpm。無(wú)論是在普通人群還是經(jīng)歷了心臟外科手術(shù)的患者中,房顫都是最為常見(jiàn)一種心律失常。流行病學(xué)研究數(shù)據(jù)顯示,在歐裔人群中房顫的總發(fā)病率達(dá)1%,中國(guó)人群中總發(fā)病率約0.77%,而在80歲以上人群中則高達(dá)8%。更為嚴(yán)重的是,房顫會(huì)顯著增加腦卒中(5倍)和心衰(3倍)的發(fā)生風(fēng)險(xiǎn),也使得心源性猝死發(fā)生率增高2.14-3.26倍。因此,房顫已經(jīng)嚴(yán)重影響人類(lèi)健康。 已有研究發(fā)現(xiàn),炎癥反應(yīng)(inflammatory)在房顫疾病的起始和維持過(guò)程中起到非常關(guān)鍵的作用。然而,在此過(guò)程中,炎癥反應(yīng)具體充當(dāng)什么樣的角色,到底是房顫發(fā)生的原因,還是房顫導(dǎo)致的結(jié)果,仍然具有爭(zhēng)論。此外,炎性反應(yīng)和炎癥信號(hào)通路影響房顫的具體分子機(jī)制仍不明確。髓過(guò)氧化物酶(Myeloperoxidase. MPO)是一種含鐵血紅素,由白細(xì)胞生成,其作用是在過(guò)氧化氫的作用下發(fā)生反應(yīng)生成次氯酸(HOC1),次氯酸在細(xì)胞內(nèi)的主要作用是調(diào)控基質(zhì)金屬蛋白酶(matrix metalloproteinases, MMP)活性,這一通路已發(fā)現(xiàn)與心房結(jié)構(gòu)性重構(gòu)關(guān)聯(lián)緊密。動(dòng)物模型研究中發(fā)現(xiàn),與野生型小鼠相比,經(jīng)血管經(jīng)張素Ⅱ處理的MPO敲除鼠會(huì)引起白細(xì)胞激活,心房組織中MPO的催化產(chǎn)物3-氯酪氨酸減少,降低MMP活性,進(jìn)而表現(xiàn)為心房肌纖維化程度大大減弱。經(jīng)右心房電生理刺激后,MPO基因敲除鼠可極大程度避免電刺激引發(fā)的房顫。而當(dāng)MPO基因重新導(dǎo)入后這種情況會(huì)被逆轉(zhuǎn)。此外,相關(guān)研究也發(fā)現(xiàn),房顫患者血漿MPO濃度與非房顫對(duì)照相比明顯升高,右心房組織中MPO大量沉積。盡管如此,MPO基因與房顫的關(guān)聯(lián),到目前為止還沒(méi)有在大規(guī)模人群中得到驗(yàn)證,缺乏最關(guān)鍵可信的遺傳學(xué)證據(jù)。 為探索MPO基因是否在遺傳學(xué)上與房顫的發(fā)生關(guān)聯(lián),在本課題中,我們?cè)贕eneID基因庫(kù)中選取了兩個(gè)單獨(dú)的中國(guó)漢族人群房顫病例-對(duì)照樣本群體,然后選取了一個(gè)MPO基因啟動(dòng)子或表達(dá)調(diào)控區(qū)域內(nèi),與MPO基因表達(dá)量顯著相關(guān)的轉(zhuǎn)錄調(diào)控型單核苷酸多態(tài)性(SNP)位點(diǎn)rs2243828作為我們研究的目標(biāo)。同時(shí),這一SNP與MPO血漿含量顯著相關(guān)。在兩個(gè)獨(dú)立群體中進(jìn)行了基因分型,并進(jìn)行了關(guān)聯(lián)性研究。結(jié)果顯示,在第一個(gè)發(fā)現(xiàn)群體(694房顫患者和710房顫對(duì)照)中,rs2243828不同基因型在病人和對(duì)照中存在顯著差異,rs2243828的G等位對(duì)于房顫的發(fā)生具有顯著地保護(hù)性作用(觀測(cè)P-obs=7.65×10-3,矯正后P-adj=6.25×10-3,矯正后OR為0.77)。在另一個(gè)獨(dú)立的復(fù)制性群體中(1,106房顫患者和1,501對(duì)照),這一結(jié)果得到了可靠的復(fù)制,rs2243828同樣發(fā)現(xiàn)與房顫顯著相關(guān)(觀測(cè)P-obs=7.28×10-5,矯正后P-adj=9.88×10-5,OR為0.75)。以上結(jié)果充分顯示,MPO基因啟動(dòng)子區(qū)域SNPrs2243828與中國(guó)人群房顫發(fā)生風(fēng)險(xiǎn)顯著相關(guān)。 Rs2243828位于MPO基因啟動(dòng)子區(qū)域,在177例健康人群中,我們研究了Rs2243828是否影響血清中MPO含量,結(jié)果顯示,G等位攜帶者血清平均MPO含量約為A等位攜帶者的50%(P=1.16x10-4)。此外,通過(guò)分層分析還發(fā)現(xiàn),Rs2243828在患有高血壓的亞群體中具有更強(qiáng)的效應(yīng),提示其在影響房顫的過(guò)程中,可能與高血壓存在相互作用。 通過(guò)以上研究,我們首次發(fā)現(xiàn)炎癥通路中的重要基因MPO啟動(dòng)子區(qū)域SNPRs2243828與中國(guó)漢族人群房顫風(fēng)險(xiǎn)顯著關(guān)聯(lián),同時(shí)還發(fā)現(xiàn)其影響房顫的分子機(jī)制可能是通過(guò)影響基因的表達(dá)和血清中MPO含量來(lái)實(shí)現(xiàn)的。我們的研究提示炎癥反應(yīng)在房顫的發(fā)生過(guò)程中起到了非常關(guān)鍵的作用,提示炎癥反應(yīng)有可能成為房顫預(yù)防、診斷以及治療的新的靶點(diǎn)。
[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.
【學(xué)位授予單位】：華中科技大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類(lèi)號(hào)】：R541.75

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