砷暴露地區居民同半胱胺酸代謝酵素基因多形性與頸動脈粥狀硬化之相關性研究

The association between carotid atherosclerosis and genetic polymorphisms of homocysteine metabolite-related genes among residents in arsenic-endemic area

徐憶驊(Yi-Hua Hsu)

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/碩士(2002年)

摘要

無機砷是人類已知的致癌物質，對於無機砷的危害效應，有許多研究已加以證實。它會導致高血壓、缺血性心臟病、週邊血管疾病及烏腳病、動脈血管系統的相關疾病。目前已知動脈血管粥狀硬化是血管疾病重要的次臨床症狀。除砷暴露的危害外，還有其它危險因子也會導致動脈血管粥狀硬化的產生，如：抽菸、高血壓、高濃度的LDL-C及同半胱胺酸（hcy）。許多研究指出血漿中同半胱胺酸濃度升高會導致動脈血管粥狀硬化、中風、缺血性心臟病、周邊血管疾病等;同半胱胺酸濃度與其代謝機制有密切關係，所涉及之代謝相關酵素基因型、活性及營養狀況等因素均會影響代謝機制之正常與否。因此探討無機砷暴露、同半胱胺酸代謝酵素基因多形性與頸動脈粥狀硬化的關係，有助於了解砷致動脈粥狀硬化性的機轉。本研究以190位蘭陽盆地砷暴露地區經判定為粥狀動脈硬化的病人為個案，依年齡配對方式選出190位非粥狀動脈硬化者為對照組，共380位。以聚合酵素連鎖反應（PCR）增幅甲烯基四氫葉酸還原酵素（MTHFR）、甲硫胺酸合成酵素（MS）及轉硫化酵素（CBS）的基因片段，再以限制片段長度多形性（RFLP）來做基因多形性的分析。結果：典型的頸動脈粥狀硬化危險因子：高LDL/低HDL、高總膽固醇、高三酸甘油脂、高血壓及糖尿病患者均具有較高的罹病危險性，其中總膽固醇有劑量-效應關係。血漿中同半胱胺酸及飲水砷濃度與頸動脈粥狀硬化之間也具相關且同樣有劑量-效應關係。在與飲水砷濃度或累積砷暴露做多變項及交互作用分析之後，發現環境中砷暴露對頸動脈粥狀硬化的危險性較基因型對頸動脈粥狀硬化的影響明顯。另外，MTHFR C677T、MS A2756G或CBS T833C/INS68與頸動脈粥狀硬化罹病危險性並無顯著相關，且砷暴露與三酵素基因型對頸動脈粥狀硬化的影響可能是互相獨立的。

關鍵字

砷 ； 同半胱胺酸 ； 甲烯基四氫葉酸還原酵素 ； 甲硫胺酸合成酵素 ； 轉硫化酵素

並列摘要

The atherogenic and carcinogenic effect of inorganic arsenic has been well documented significant associations between arsenic exposure and risks of hypertention, ischemic heart disease (IHD), peripheral vascular disease, blackfoot and other artery-related disease were observed in many epidemiologic studies. Atherosclerosis is an important subclinical symptom of blood disease. Many factors including smoking, hypertention, high LDL-chol and plasma homocysteine (hcy) have been reported to increase the risk of atherosclerosis. In addition, many epidemiological studies reported that elevated plasma hcy concentrations would increase the occurance of atherosclerosis, stroke, IHD, peripheral vascular disease,etc. High plasma hcy level might be caused by genetic defects and/or nutrient deficiencies. The specific aim of this study is to explore the relationship between inorganic arsenic exposure, genetic polymorphisms of hcy metabolite-related genes and carotid atherosclerosis. This study area included 18 villages of Lanyang Basin located on the northeastern coast of Taiwan. A total of 190 residents of study area were randomly selected as carotid atherosclerosis patients based on their health examination reported with IMT≧0.8 mm or plaque score1, another 190 age matched control were also recruited with their health examination report with IMT≦0.8 mm and plaque score<1. Genetic polymorphisms of MTHFR C677T, MS A2756G, CBST833C/INS68 were detected by PCR and RFLP. Logistic regression analysis was used to estimate risks of carotid atherosclerosis induced by various risk factors and their 95% confidence interval. The results showed that study subjects with high level of serum LDL-chol, total cholestrol, triglyceride and hcy, and history of hypertention and diabetes had higher risk for the development of carotid atherosclerosis. A dose-response relationship between total chol, plasma hcy, arsenic concentration in well water and risk of carotid atherosclerosis was also observed. A higher risk for the development of carotid atherosclerosis who found among study subjects carried varient genetic type of MTHFR, wild genetic type of MS, non insertion of CBS. In addition, a significantly synergistic effect for the development of carotid atherosclerosis and genetic polymorphisms of MTHFR, MS, CBS dose not observed in this study.

並列關鍵字

Arsenic exposure ； Homocysteine ； MTHFR ； MS ； CBS

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