探討血清中與缺血性中風發展相關之脂氧素－巢式病例對照研究

Identification of Serum Oxylipins Associated with Development of Ischemic Stroke ─ a Nested Case Control Study

楊晉安(Chin-An Yang)

指導教授 ： 潘文涵

國立臺灣大學/生命科學院/生化科技學系/碩士(2019年)

https://doi.org/10.6342/NTU201903256

摘要

背景：中風是最常見的心血管疾病之一，也是世界各地導致死亡或身體失能後遺症的主要原因之一。在台灣，中風為十大死因中的第三名。而缺血性中風占了所有中風案例中超過百分之八十的比例。長期以來脂肪酸的攝取被認為和心血管疾病的發生有相當的關係，其中多元不飽和脂肪酸經由氧化後代謝出的脂氧素(Oxylipin)類分子參與了許多發病機制。過去研究中仍未有針對脂氧素及缺血性中風之間關係的研究。因此，本研究以目標性代謝體學的方法，希望能夠找出和缺血性中風相關的脂氧素分子，並探討其可能的機制，以及期望進一步了解中風機制並改善缺血性中風的風險預測模型。
材料與方法：本研究為巢式病例對照研究設計，研究對象來自於竹東及朴子地區心臟血管疾病長期追蹤研究 (CVDFACTS, the CardioVascular Disease FACtor Two-township Study)。針對1991-1993年間收集之5148名基線個案，當中挑選了62位在1993-2002年健保資料庫被記錄發生過缺血性中風的患者為病例組，並以年齡、性別等條件配對出221個健康對照組。以案例在基線收集之血清樣本進行脂氧素代謝體分析，並用條件式單變數羅吉斯迴歸分析搭配共變數校正，篩選出與疾病相關之脂氧素。進一步以多變數羅吉斯迴歸分析及因素分析探討脂氧素分子之間的關係及對疾病影響之獨立效應。接收者操作特徵曲線下面積(area under ROC curve)則用來評估缺血性中風之風險預測模型。
結果：研究一共發現9種脂氧素分子與缺血性中風有相關，其中9-oxo-ODE、13-oxo-ODE、5-oxo-ETE、15-oxo-ETE為降低缺血性中風之風險；20-HETE、11,12-DHET、PGB2/PGJ2、10,17-DiHDoHE、EPA為增加缺血性中風之風險。以傳統預測缺血性中風之因子配合9種脂氧素的模型，相對與傳統預測因子模型，能有效提升對於疾病的預測風險達6%。
結論：9種脂氧素分子中，9-oxo-ODE及13-oxo-ODE已知為氧化態低密度脂蛋白(oxLDL)中重要的成分，其功用也與動脈粥狀硬化有相關。5-oxo-ETE已知能增進嗜酸性球及中性球細胞的流入，提高過敏及發炎疾病的可能性；而15-oxo-ETE則是被研究有抗發炎、抑制細胞增生的作用。20-HETE的含量在易發生缺血性中風的動物模式中有顯著提高；11,12-DHET含量則與上游的可溶性環氧化物水解酶表現(sEH)有關。10,17-DiHDoHE為DHA的氧化產物，與EPA在目前已知的研究中都呈現對於心血管疾病具有保護作用。在本次研究中則無法進一步區分PGB2/PGJ2分子的不同。本次研究確認了脂氧素類分子與缺血性中風的相關性，也更進一步對於預測缺血性中風之風險提供了新的方向。

關鍵字

缺血性中風 ； 目標性代謝體學方法 ； 多元不飽和脂肪酸 ； 脂氧素 ； 巢式病例對照研究 ； 預測

並列摘要

Background：Stroke is one of the most common cardiovascular diseases, and also a major cause of death and disability worldwide. Ischemic stroke accounts for over 80 percent of all strokes. oxylipins, representing a family of oxidized polyunsaturated fatty acids, are associated with cardiovascular diseases and involve many pathological mechanisms. In view of few epidemiology studies examined the association between oxylipins and ischemic stroke, we investigated association between oxylipins and ischemic stroke with the goal to improve the ischemic stroke prediction risk model.
Materials and Methods：We designed a nested case control study, taking advantage of the data from CVDFACTS, a community based longitudinal cohort study designed to study risk factors and evaluation of cardio-metabolic diseases in Taiwan. We selected 62 new-onset ischemic stroke cases recoded in the National Health Insurance Research Database and 221 age and gender matched controls who were chosen from those who did not develop ischemic stroke. Their baseline fasting serums were used for metabolomics study. We selected the oxylipin compounds associated with ischemic stroke by using uni-variate logistic regression with covariates adjustment. Multi-variate logistic regression and factor analysis were used to understand the association and effect sizes between oxylipins and the disease. ROC curve was used to generate risk assessment model for predicting ischemic stroke risk.
Results：We found 9 oxylipins associated with development of ischemic stroke：9-oxo-ODE、13-oxo-ODE、5-oxo-ETE、15-oxo-ETE are protective factors; 20-HETE、11,12-DHET、PGB2/PGJ2、10,17-DiHDoHE、EPA are risk factors. With the comparison to traditional risk factors model, the model which contains traditional risk factors and 9 oxylipins performed significantly better in the ROC curve result for ischemic stroke prediction.
Conclusion：Among 9 oxylipins found in this study, 9-oxo-ODE and 13-oxo-ODE are known as major components in the oxLDL, and associated with atherosclerosis. With two oxo-ETEs, 5-oxo-ETE can increase macrophages and monocytes influx to the cell, associated with allergic and inflammatory diseases. On the other hand, 15-oxo-ETE can result in anti-inflammatory effects. In a spontaneously hypertensive stroke-prone rat model, 20-HETE was elevated to increase susceptibility to ischemic stroke. The 11,12-DHET content is associated with the up-stream enzyme, sEH. The 10,17-DiHDoHE is one of DHA down-stream oxylipins. EPA and DHA are both known as protective factors to cardiovascular diseases. Only the PGB2/PGJ2 peak cannot be identified in this study. We performed a new model to assess the ischemic stroke risk perdiction. A significant improvement is achieved compared to the traditional risk factor model.

並列關鍵字

Ischemic stroke ； targeted metabolomics approach ； polyunsaturated fatty acid ； oxylipin ； nested case-control study ； prediction

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