台灣西南沿海高砷暴露地區與非暴露地區之心電圖異常與心血管疾病死亡率:基因與環境交互作用之研究

Electrocardiogram (ECG) abnormality and cardiovascular mortality among residents in arseniasis-endemic and non-endemic areas of southwestern Taiwan: A study of gene-gene and gene-environment interactions

廖雅堂(Ya-Tang Liao)

指導教授 ： 陳為堅

共同指導教授 ： 陳建仁 ； 王淑麗(Shu-Li Wang)

國立臺灣大學/公共衛生學院/流行病學與預防醫學研究所/博士(2011年)

https://doi.org/10.6342/NTU.2011.00707

摘要

心臟及血管疾病為世界各地主要的致死原因之一，危險因子相對風險之些微的提升即會造成很顯著的死亡人口的增加。砷是已明確證明主要與心血管疾病以及惡性腫瘤有關但是可經由後天修飾的一種環境污染物質。砷所造成的心血管疾病可能由遺傳因子與環境因子的毒性機制所共同作用的結果，然而對於心血管疾病死亡率提高多少是歸因於遺傳因子所造成目前仍無充分資料。目前已有許多已發表慢性砷暴露與心血管疾病之關連性研究，但大部份僅限於橫斷型的研究設計而較缺乏長期追蹤的科學證據。此外，絕大部份研究專注在探討砷所引起之臨床心血管疾病，而較少研究討論疾病發展之前期或早期的臨床表現。因此，使用這些前期及早期臨床表徵來評估砷所造成的慢性中毒有其重要性。本研究之主要目的即欲探討巴拉松酶(Paraoxonase, PON1)、三價砷甲基化酶(AS3MT)以及榖胱苷肽硫轉移酶(GSTO1)等基因以及慢性砷暴露作用於乳酸去氫酶(Lactate dehydrogenase, LDH)以及心電圖異常等臨床前期表現之加成效應，並檢驗砷代謝能力是否會調節砷所造成的心血管疾病風險。根據我們的結果顯示，即使在停止慢性砷暴露數十年之後，心血管疾病之臨床前期指標仍與暴露量存在某種程度的關連，顯示砷之長期的健康危害。而在停止暴露若干年之後，尿中砷代謝之物種更能反應長期砷暴露之指標。此外，本研究發現顯著作用於臨床前期之基因與基因，基因與環境交互作用。這些結果可以提供目前砷暴露地區之飲用水風險管控提供重要的參考。

關鍵字

砷暴露 ； 缺血性心臟病 ； 心電圖 ； 乳酸去氫酶巴拉松酶三價砷甲基化酶榖胱苷肽硫轉移酶

並列摘要

Cardiovascular disease is a major cause of mortality worldwide, small increase in odds ratio may result in significant excess number of deaths. Arsenic is a potent but modifiable environmental pollutant that has been linked to increased prevalence of cardiovascular disease (CVD) and cancer globally. Arsenic-induced CVD may result from the inter-correlations among genetic, environmental factors though toxicological mechanisms. However much less was known about the excess mortality from arsenic with genetic factors considered. Although an association between chronic arsenic exposure and CVD has been found in many studies, nearly all of these studies were limited by use of cross-sectional data, and longitudinal evidence by follow-up study was still limited. Besides, majority of previous studies were focus on the clinical arsenic-related cardiovascular disease, instead of the manifest of preclinical or subclinical detections. Studies based on subclinical finding are needed to detect the early sign of chronic poisoning. The objective of this study is to investigate the joint contribution of genetic factors including PON1, AS3MT, and GSTO gene families and the long-term arsenic impacts on cardiovascular disease through measuring plasma LDH levels and ECG abnormality as subclinical phenotypes and to evaluate whether the arsenic methylation patterns modifies the association between cumulative arsenic exposure and the risk of CVD. Our studies demonstrated after cessation of arsenic-contaminated water consumption for decades, biomarkers for CVD mortality and morbidity was still associated with reduced risks for arsenic. Arsenic methylation profiles appeared to become more efficient among subjects after cessation of long-term exposure to high levels of arsenic. Besides, this study also illustrated significant gene-gene interaction and gene-environment on early effect markers for CVD. These results may have implications for arsenic mediation strategies in areas currently exposed to potentially harmful levels of arsenic in drinking water.

並列關鍵字

Arsenic exposure ； Ischemic heart disease ； Electrocardiogram ； Lactate dehydrogenase ； Paraoxonase ； Arsenic methyltransferase ； Glutathione S-transferases omega

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