eNOS G894T基因多型性在中老年男性健康之易感性研究- 含勃起功能障礙、良性前列腺肥大相關之下泌尿道症狀與代謝症候群

The study of eNOS G894T genetic susceptibility on aging men’s health- erectile dysfunction, benign prostate hyperplasia related lower urinary tract symptoms and metabolic syndrome

李永進(Yung Chin Lee)

指導教授 ： 黃俊雄

高雄醫學大學/醫學院/醫學研究所/博士(2012年)

摘要

在中老年族群當中，勃起功能障礙、前列腺肥大相關之下泌尿道症狀及代謝症候群為三個影響男性健康的常見疾病。由於這些疾病的盛行率皆隨著年齡增加而上升，隨著近年來全球人口的逐漸老化，這些疾病之間的關連性已經受到越來越多學者的重視。
雖然已有一些研究顯示上述這些疾病之間存在著關連性，但由於年齡及其它相關的共病因子，在研究中多半未受到嚴謹的控制，使得這些研究結果仍存在一些限制。此外，上述疾病在不同的族群之間，於流行病學上的表現有著相當的差異性，而先前這方面的研究大多來自西方國家，針對亞洲族群所作的研究，至今仍是十分有限。再者，這些研究並無對於疾病的致病機轉提供進一步的說明(例如：疾病間是否為因果關係？抑或共同起因於第三病源)。因此，最近的研究也慢慢朝向探究這些疾病的病源，並且著重於共同的致病機轉。
在本論文的第一章，我們研究了台灣中老年男性族群之代謝症候群對勃起功能障礙的影響。藉由舉辦社區民眾健康篩檢的方式，一共收集639位平均年齡60.2歲的個案，完整收集臨床的資料及問卷調查結果加以分析。代謝症候群的診斷，則採用台灣國民健康局制訂的標準。利用多變項邏輯迴歸分析後，研究結果顯示：患有勃起功能障礙的族群，其代謝症候群的盛行率顯著較高(p<0.01, OR=2.30)；而患有代謝症候群的族群，其五項勃起功能國際指標分數則顯著較低，且分數隨著個案所具有代謝症候群的因子數目增加而降低(p<0.01)。進一步分析發現，五個代謝症候群的因子當中，空腹血糖值異常是對於勃起功能障礙最顯著的獨立影響因子(p=0.01, OR=1.60)。
勃起功能障礙、前列腺肥大相關之下泌尿道症狀及代謝症候群都是多重病因的疾病，其中很可能也包含著先天遺傳因素的影響。雖然已有少數的研究顯示這些疾病的致病機轉可能受基因的影響，然而，對於哪些共同基因同時影響這些疾病，至今了解仍是十分有限。
目前已知，一氧化氮(NO)在陰莖組織的勃起功能上佔有著重要角色。此外，有一些足以影響NO生成的重要酵素，例如內皮性一氧化氮合成酶(eNOS)，其基因分子表現也被證實存在於人類的前列腺組織中。而過去的研究顯示，位於eNOS基因上的G894T多型性，會影響eNOS的酵素活性及之後NO的生成，因此在本論文的第二章，我們研究eNOS G894T基因多型性與勃起功能障礙及前列腺肥大相關之下泌尿道症狀之間的關連性。總共收集372位平均年齡60.2歲的男性個案加以研究。病人之eNOS G894T基因多型性的檢測，採用聚合酶連鎖反應-限制酶片段長度多型性的方法。利用多變項邏輯迴歸分析，研究結果顯示：年齡老化、糖尿病與eNOS 894T對偶基因型是三個影響勃起功能障礙及前列腺肥大相關之下泌尿道症狀的共同獨立危險因子(p<0.05)。而具有T對偶基因型(GT/TT)族群，其勃起功能障礙(p=0.012)及前列腺肥大相關之下泌尿道症狀(p=0.004)的盛行率，顯著高於具G對偶基因型(GG)的族群。在嚴重度方面，前者亦顯著高於後者，其結果顯示：eNOS G894T基因多型性可能在這兩個疾病的基因易感性上，扮演著某些特別意義。
胰島素抗性是代謝症候群的主要病因。目前已有許多的研究證據指出：胰島素抗性與人體內皮細胞功能異常關係十分密切，進而使得NO的合成製造受到阻礙，據推論這樣的機轉可能是造成勃起功能障礙與代謝症候群的共同病因。在本論文的第三章，我們更進一步研究eNOS G894T基因多型性在勃起功能障礙與代謝症候群上是否具有基因易感性。總共收集590位平均年齡55.3歲的個案加以研究。我們的結果顯示：具有T對偶基因型族群，其代謝症候群(p=0.02, OR=1.64)及勃起功能障礙(p=0.01, OR=1.76)的盛行率，顯著高於具G對偶基因型的族群；而在勃起功能嚴重度及其代謝症候群因子數方面，前者亦明顯高於後者，而且與個案所具有的 T 對偶基因數目有顯著相關(p<0.05)。
本篇論文的研究結果顯示：在台灣中老年男性族群當中，勃起功能障礙、前列腺肥大相關之下泌尿道症狀與代謝症候群三者間具有關連性，且均與eNOS G894T基因多型性相關，其中，具有T對偶基因型的族群，有著較高患病的危險性。這樣的結果顯示：eNOS G894T基因多型性可能在這三個相關疾病之共同基因易感性上，存在著某些意義。然而這些影響男性健康疾病的基因易感性，其分子生物層次的致病機轉為何，仍有待未來更多前瞻性與功能性的研究進一步探討。

關鍵字

基因多型性 ； 勃起功能障礙 ； 良性前列腺肥大 ； 代謝症候群

並列摘要

In aging population, erectile dysfunction (ED), benign prostate hyperplasia related lower urinary tract symptoms (BPH/LUTS) and metabolic syndrome (MtS) are three remarkably common problems affecting men’s health. Since the prevalence of ED increases with age, which is overlap BPH/LUTS and MtS in aging patients, there has been increasing interest in the associations among these disorders, provoked by the expanding population of the elderly over the past years.
Despite the accumulated evidence has suggested the links for these disorders, some limitations still remained in assessing the correlations because of poorly controlling the effects of age and other comorbidities. In terms of epidemiology, the expression of theses disorders is considerable variable among ethnicities. Studies about this issue mainly appeared for western ethnicities to date; however, data from Asian populations were still limited. Furthermore, these studies cannot provide further evidence about the possible mechanisms of disease etiology, such as being unable to reveal whether one disorder causes the other or a third factor causes both. Therefore, recent investigations have continued into the etiology of each other, with particular attention being paid to the common pathway.
In the first chapter, we aimed to determine the potential impact of MtS on ED in aging Taiwanese males. A total of 639 subjects with a mean age of 60.2 (range 40–83) years were enrolled during a free health screening. All the men had complete clinical data and questionnaires taken. The definition of MtS was according to the criteria of the Bureau of Health Promotion in Taiwan. Using age-adjusted multivariate logistic regression analysis, our results showed that subjects with ED had significantly higher prevalence of MtS (p<0.01, OR=2.30). The presence of MtS had significant correlation with lower IIEF- 5 scores, which were associated with the increment of MtS components number (p<0.01). Among the MtS components, abnormal fasting blood glucose was the most significantly independent factor of MtS for ED (p=0.01, OR=1.60).
All of ED, BPH/LUTS and MtS are a multifactorial disturbance that potentially includes hereditary components of structural and regulatory proteins involved in their pathogenesis. Few studies have suggested a heritable basis to the etiologies. However, there is still a very limited understanding about common genetic factors influencing these disorders.
To date, the pivotal role for nitric oxide (NO) pathway in the relaxation of male penile erectile tissue has been widely accepted. The expression of key enzymes of the NO production, such as endothelial NO synthase (eNOS), in human prostate has also been well demonstrated. A common G894T polymorphism of the gene eNOS, which encoded for eNOS enzyme, was reported to cause a disturbance of eNOS enzyme activity and NO production. In the second chapter, we aimed to investigate the associations among eNOS G894T polymorphism, ED and BPH/LUTS. A total of 372 men had a mean (SD) age of 60.2 (8.8) years were enrolled. The eNOS G894T polymorphisms were determined using the polymerase chain reaction-restriction fragment length polymorphism method. With multivariate analysis, our data identified that aging, DM and eNOS 894T allele were the three independent common risk factors for both ED and BPH/LUTS (P<0.05). The eNOS 894T allele carriers (GT/TT) had significantly higher prevalence of ED (P =0.012) and BPH/LUTS (P =0.004) than G allele carriers (GG). Also the T allele carriers had higher severities of both disorders, suggesting that eNOS G894T gene polymorphisms may play an implication as a genetic susceptibility factor for both disorders.
Insulin resistance (IR) is the core of the MtS. Accumulated evidences have outlined the potential relation between IR and endothelial dysfunction, which impaired endothelial ability to synthesize or release NO, might provide a common pathophysiological mechanism of ED and MtS. In the third chapter, we aimed to investigate the genetic susceptibility of eNOS G894T polymorphisms underlying the development of both disorders. A total of 590 subjects with a mean (SD) age of 55.3 (4.1) years were enrolled. Our results showed that the eNOS 894T allele carriers had significantly higher prevalence of MtS (p=0.02, OR=1.64) and ED (p=0.01, OR=1.76) than G allele carriers after adjustment for each other and age. Also the T allele carriers had significantly lower IIEF-5 score and more MtS components, which were significantly associated with an increment of the T allele number (p<0.05).
Our studies confirmed the associations among ED, BPH/LUTS and MtS in the aging Taiwanese men. The eNOS 894T allele carriers are at greater risk for these disorders independent of each other and age, suggesting that eNOS G894T gene polymorphisms may play an implication as a common genetic susceptibility factor for these disorders. However, further prospective and functional studies are needed to investigate the underlying molecular mechanisms that confer the impact of genetic susceptibility on these disorders affecting men’s health.

並列關鍵字

gene polymorphism ； erectile dysfunction ； benign prostate hyperplasia ； metabolic syndrome

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