雌激素、發炎因子及其基因多形性、血壓控制與缺血性中風之相關性研究

Estrogen, inflammation and their genetic polymorphisms, and blood pressure control associated with risk of ischemic stroke

謝宜蓁(Yi-Chen Hsieh)

指導教授 ： 邱弘毅

臺北醫學大學/公共衛生暨營養學院/公共衛生學研究所/博士(2009年)

摘要

腦中風疾病在台灣是列為第三大死因。同時它也是成年人失能的最主要原因。許多研究指出雌激素與心血管疾病的危險性有相關，且扮演著抗發炎的角色。為探討雌激素與中風的相關性，本研究之目的分別為：第一在分析台灣缺血性中風發生個案數在加權台灣人口數之後女性是否隨著年齡越高越接近於男性。第二在探討內生性的雌激素暴露與罹患中風危險性的關係。第三在探討雌激素接受體（estrogen receptor-α[ESR1]、esrtrogen receptor-β[ESR2]）與發炎因子單核球化學趨附蛋白-1（monocyte chemoattractant protein-1, MCP-1）、E-選擇性蛋白（E-selectin）和P-選擇性蛋白（P-selectin）基因多形性與缺血性中風危險性之相關性。此外，由於停經後女性高血壓發生率提高可能與雌激素的改變有關，且高血壓亦是缺血性中風之一重要危險因子，故本論文第四部份的目的為以公共衛生預防之角度，探討以家庭為基礎之衛教介入的方式來控制血壓，期能降低日後中風的危險性。
第一個部份的研究係利用2006年9月1日至2008年10月31日止之台灣中風登錄資料，此資料庫係由台灣37家醫院一起參與。所有中風病人均經由電腦斷層掃瞄（CT）或核磁共振攝影（MRI）的診斷確認。共有17,204位缺血性中風病人進入分析。第二和第三部份的研究之病例組是收集來自於宜蘭羅東博愛醫院、台南奇美醫院、台北醫學大學附設醫院、萬芳醫院與新光醫院之缺血性中風病人。對照組則選自由國民健康局補助之「臺北醫學大學文山區中風防治中心先趨性計畫」所建立之1,647位追蹤世代，由其中選取年齡性別配對且未罹患中風之健康個案。所有參與者均接受結構式問卷訪談，內容包括生活習慣、抽菸喝酒史、初經與停經歲數及賀爾蒙補充藥物使用情形及個人疾病史。基因多形性分析則是利用聚合酶連鎖反應（polymerase chain reaction, PCR）與限制片段長度多形性方法（restriction fragment length polymorphism, RFLP）。利用多變項邏輯式迴歸分析缺血性中風危險性與雌激素暴露時間和雌激素接受體與發炎相關基因多形性的關係。第四部份的研究對象為上述所建立之追蹤世代，以家庭介入的衛教模式，觀察其6個月後之血壓變化情形。
第一部份的結果指出在調整缺血性中風之危險因子如高血壓、糖尿病、腦血管疾病史、血脂異常、暫時性腦缺血發作疾病史、心臟疾病史、尿毒症、中風家族史、高血壓家族史、糖尿病家族史、缺血性心臟病家族史、肥胖與不運動之後，年齡在45歲至59歲之間，女性罹患缺血性中風之危險性是男性的0.6倍，達統計上顯著意義。年齡層在60歲至79歲之間，男女性得到缺血性中風的危險性相差不多，但在80歲以後則是女性比男性較易罹患缺血性中風（OR=1.7, 95% CI=1.3-2.3）。此外，在加權台灣的人口分佈之後，女性中風個案數比上男性中風個案數之比例，不論是全部的中風病人或是只有缺血性中風病人，此比例有隨年齡增加而上升的情形，尤其在60歲以後有加速上升的趨勢，而在80歲以後則是女性個案數多於男性。第二部份結果發現在調整年齡及教育程度之後，相較於初經年齡在16歲以後之婦女，初經於13歲至15歲之間者罹患缺血性中風的危險性為0.5倍；初經年齡小於13歲者危險性為0.3倍，均具有顯著的保護作用。進一步以逐步邏輯式迴歸分析發現教育程度多於13年、初經年齡小於13歲及常攝食豆類食品者會顯著降低缺血性中風罹病危險性；而具有糖尿病史及腰圍大於等於80公分者則有顯著較高缺血性中風罹病危險性。第三部份結果則觀察年齡大於等於60歲之研究個案，有較低的雌二醇濃度且具有一個以上之MCP-1（A-C）、CCR2（T-C）、P-selectin（C-A-C）、E-selectin（A-G-T-C）、ESR1（T-A）和ESR2（T-G）危險性單套型基因者，相較於雌二醇濃度高且不具危險性單套型者，均有顯著的缺血性中風危險性；惟在女性之ESR1基因無觀察到同樣的結果。第四部份之結果為在衛教介入組中收縮壓於高血壓前期個案下降了2.0 mmHg，高血壓患者下降了5.9 mmHg。此外，衛教介入組個案可藉由控制膽固醇、LDL、體重以及改善蔬菜水果之飲食習慣是可以顯著降低血壓。
從上結果可得知在調整缺血性中風之相關危險因子之後，年齡越大，女性罹患缺血性中風的危險性會逐漸較男性高，推測與停經後雌激素改變有相關。進一步觀察到初經較早者，亦即越早暴露雌激素者有較低的危險性。而且雌激素與其接受體及發炎因子基因多形性可以修飾雌二醇濃度對於缺血性中風之易感受性。由以上的研究結果顯示雌激素對於缺血性中風具有保護效果。同時，本研究亦獲得以家庭為基礎之衛教介入對於沒有服用高血壓藥物治療之高血壓患者，可以顯著降低收縮壓與舒張壓，達到預防中風之成效。

關鍵字

雌激素 ； 缺血性中風 ； 雌激素接受體 ； 單核球化學趨附蛋白-1 ； E-選擇性蛋白 ； P-選擇性蛋白 ； 血壓 ； 衛教介入

並列摘要

Cerebrovascular diseases are the third leading cause of death in Taiwan in 2008, and the most important cause for disability among elderly adults. Sex hormones are associated with cardiovascular disease. Several studies found that estrogens have beneficial effects on the cardiovascular system such as anti-inflammation. The purpose of this study were 1) to examine whether the increasing of ischemic stroke cases of female is more quickly than that of males among subjects with age ≥60 after weighting by Taiwan whole population; 2) to explore the association between endogenous estrogen exposure and the risk of ischemic stroke; 3) to investigate the relationship between polymorphisms of estrogen receptors (estrogen receptor-α [ESR1], esrtrogen receptor-β [ESR2]) and inflammatory genes (monocyte chemoattractant protein-1 [MCP-1], E-selectin, P-selectin) and ischemic stroke. Furthermore, hypertension is one of the most important risk factors of ischemic stroke and had been found to be associated with estrogen exposure. The final purpose of this study is to elucidate the effect on lowering blood pressure through a family-based health education programme among hypertensive patients and pre-hypertensive subjects without taking any antihypertensive drugs.
The study subjects of part I study were recruited from Taiwan stroke registry data bank through September 1st, 2006 to October 31st, 2008 which was included by 37 major hospitals in Taiwan. All stroke patients were diagnosed by computed tomography (CT) or magnetic resonance imaging (MRI). There were 17,204 first-ever stroke patients were included in this part I study. The ischemic stroke patients of part II and part III studies were recruited from Lotung Poh-Ai Hospital, Chi Mei Medical Center, Taipei Medical University Hospital, Wan Fang Hospital, Shin Kong Wu Ho-Su Memorial Hospital. The stroke-free healthy controls were age- and gender-matched and selected from 1,647 community-based cohorts. All participants were interviewed through structured questionnaires including lifestyle, history of cigarette smoking and alcohol drinking, age of menarche and menopause, hormone replacement treatment history, and disease history. Estrogen receptors and inflammatory genes were genotyped using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method. A multivariate logistic regression model was used to estimate the relationship between ischemic stroke and estrogen exposure and polymorphisms of estrogen receptor and inflammatory genes. The study subjects of part IV were from the community-based cohort which described above. Family-based health education was developed to provide strategies for lowering blood pressure. The blood pressure of study subjects was measured at baseline and 6-month follow-up to evaluate the intervention’s effect on decrease in blood pressure.
The results from part I showed that female aged between 45 and 59 years old had significantly 0.6-fold risk of ischemic stroke when compared with male after adjusting for hypertension, diabetes mellitus, cerebrovascular disease history, hyperlipidemia, transient ischemic attack history, heart disease history, uremia history, family history of stroke, family history of hypertension, family history of diabetes mellitus, family history of ischemic heart disease, obesity and physical inactivity. The ischemic stroke risk was similar between female and male among subjects aged from 60 to 79 years old. However, female had more ischemic stroke risk than male after 80 years old (OR=1.7, 95% CI=1.3-2.3). In addition, after being weighted by Taiwan population, the ratio of female and male stroke incidence was increased by age, especially for subjects greater than 60 years old. The stroke incident cases of female were greater than those of male after 80 years old. Part II study illustrated that when compared with study subjects whose menarche age greater than and equal to 16 years as referent group, a significantly decreased risk were observed in those whose menarche between the ages of 13 and 15 (OR=0.5, 95% CI=0.3-1.0) and less than ages of 13 (OR= 0.3, 95% CI=0.1-0.7). Moreover, both age at menarche less than 13 years and education level greater than 13 years played as an independent factor for decreased risk of ischemic stroke. DM, waist circumference equal and greater than 80 cm, and dietary intake of soybeans less than 3 times per week were also independently associated with increased risk of ischemic stroke when using stepwise logistic regression model.
The results from part III study found that participants aged equal and greater than 60 with lower serum estradiol level and greater than 1 copy of risk haplotypes of MCP-1 (A-C), CCR2 (T-C), P-selectin (C-A-C), E-selectin (A-G-T-C), ESR1 (T-A), and ESR2 (T-G) had significant ischemic stroke risk when compared those who had higher serum estradiol level and without any risk haplotypes. The similar result was not observed in female with ESR1 risk haplotyp. Part IV study results showed that significant decreases of 2.0 mmHg and 5.9 mmHg in systolic blood pressure were observed both in pre-hypertensive and hypertensive subjects in the intervention group. Additionally, intervention subjects with improvement of total cholesterol and LDL cholesterol, decrease in indices of body weight, and increase in consumption of fruit and vegetables also had significant lowering of blood pressure.
In conclusion, our study showed that postmenopause women had higher ischemic stroke risk than men after adjustment for stroke related risk factors. It might be associated with the change of estrogen. The study further observed that early menarche female had lower risk of ischemic stroke. Polymorphisms of estrogen receptor and inflammatory genes could modify the susceptibility of ischemic stroke. These findings suggested that estrogen could protect against ischemic stroke. In addition, the study further found that the blood pressure of pre-hypertesive and hypertensive subjecs who were without taking antihypertensive drugs could decrease their blood pressure significantly through interventions of family-based health education, showing effects on stroke risk reduction from public health approach.

並列關鍵字

estrogen ； ischemic stroke ； estrogen receptor ； monocyte chemoattractant protein-1 ； E-selectin ； P-selectin ； blood pressure ； family-based health education intervention

參考文獻

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