台灣烏腳病盛行地區高血壓與含錳超氧歧化酵素基因多形性之相關性研究

The Relationship between Manganese Superoxide Dismutase Gene Polymorphism and Hypertension in Blackfoot Disease Hyperendemic Area in Taiwan

陳惠雯(Hui-Wen Chen)

指導教授 ： 薛玉梅

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

針對烏腳病盛行地區探討含錳超氧歧化酵素（MnSOD）基因多形性和高血壓之間的關係。以30歲以上並且每週居住在研究地區至少五天的居民作為研究對象，並利用78年收集的資料以及78到86年間所採集的生物檢體。兩位公共衛生護士以結構式問卷訪視每位研究對象，問卷內容包括社會人口學資料、抽菸與喝酒習慣、職業史、居住史、飲水史與家族疾病史等項目。血球萃取出之DNA利用聚合酵素連鎖反應及限制片段長度多形性分析含錳超氧歧化酵素粒線體目標序列Val/Ala變異。利用高效率液相層析儀分析血清中微量營養元素包括維生素A、維生素E、蕃茄紅素、B—胡蘿蔔素。調整高血壓傳統危險因子及累積砷暴露後，含錳超氧歧化酵素Val/Ala和Ala/Ala基因型者，高血壓相對危險性是Val/Val基因型者的2倍，顯著偏高。調整年齡、性別、身體質量指數、累積砷暴露等重要危險子後，含錳超氧歧化酵素基因型為Val/Ala和Ala/Ala者不論三酸甘油脂及維生素E濃度為何，危險對比值有上升趨勢。調整了年齡和性別後，帶有Val/Val基因型且累積砷暴露越低、身體質量指數正常、三酸甘油脂濃度越低者，高血壓的相對危險性有下降的趨勢。調整重要危險因子後，含錳超氧歧化酵素基因型為Val/Val時，累積砷暴露在10.2 ppm*年以上者高血壓相對危險性是基因型為Val/Val時，累積砷暴露小於10.2 ppm*年者的7.9倍，呈統計上顯著性，此外，也發現累積砷暴露在10.2 ppm*年以上者，不論三酸甘油脂、低密度脂蛋白膽固醇及維生素E濃度為何，高血壓的相對危險性有上升的趨勢。因此本研究推論含錳超氧歧化酵素基因多形性可能是高血壓基因上的一個易感受性因子，基因型的不同可能修飾個體罹患高血壓的危險性，而後天環境的暴露、生活及飲食習慣更是影響高血壓相當重要的危險因子。

關鍵字

含錳超氧歧化酵素 ； 無機砷 ； 高血壓 ； 微量營養元素

並列摘要

The relationship between hypertension and manganese superoxide dismutase (MnSOD) gene polymorphism has been studied in the blackfoot disease endemic area. The study subjects who were over 30 years old and lived at least 5 days a week in the three villages were recruited. The data of study subjects were collected in 1989 and biological samples were obtained from 1989 to 1997. Two well-trained public health nurses performed a standardized personal interview based on a structured questionnaire. Information obtained from the interview included demographic characteristics, alcohol drinking and cigarette smoking, working and residential history, history of well water consumption as well as family history of hypertension. Moreover, DNA was extracted from buffy coat to analyze the Val/Ala variant in the mitochondrial targeting sequence in MnSOD gene utilizing polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). Serum was measured for all trans-retinol, a-tocopherol, lycopene,B-carotene by high performance liquid chromatography (HPLC).The relative risk of MnSOD Val/Ala and Ala/Ala genotype was twice increment than the MnSOD Val/Val genotype after adjusting the traditional risk factors of hypertension and cumulative arsenic exposure. After adjustment for age, sex, body mass index (BMI) and cumulative arsenic exposure, MnSOD Val/Ala and Ala/Ala genotype people had higher relative risk than MnSOD Val/Val genotype people in any concentration of triglyceride and vitamin E. The relative risk of hypertension for MnSOD Val/Val genotype people in lower cumulative arsenic exposure, normal BMI and lower triglyceride level was decreased after age and sex were adjusted. The odds ratios of MnSOD Val/Val genotype and cumulative arsenic exposure over 10.2 ppm*year was 7.9, and significantly higher than MnSOD Val/Val genotype and cumulative arsenic exposure lower than 10.2 ppm*year after adjusting the important risk factors. Besides, whether lower triglyceride, LDL-cholesterol and vitamin E concentration, the relative risk of hypertension was increasing in the case of people with cumulative arsenic exposure over 10.2 ppm*year. The results of this study suggested that MnSOD gene polymorphism may be a genetic susceptible factor of hypertension and MnSOD genotype may modify individual hypertension risk. Acquired environment exposure, life style and dietary habit were also very important risk factors for hypertension.

並列關鍵字

MnSOD ； inorganic arsenic ； hypertension ； micronutrients

參考文獻

1. Chen, C.J., Hsueh, Y.M., Lai, M.S., Shyu, M.P., Chen, S.Y., Wu, M.M., Kuo, T.L. and Tai, T.Y. Increased prevalence of hypertension and long-term arsenic exposure. Hypertension. 25(1): 53-60, 1995.

4. Barchowsky, A., Klei, L.R., Dudek, E.J., Swartz, H.M. and James, P.E. Stimulation of reactive oxygen, but not reactive nitrogen species, in vascular endothelial cells exposed to low levels of arsenite. Free Radical Biology & Medicine. 27(11-12): 1405-1412, 1999.

5. Lynn, S., Gurr, J.R., Lai, H.T. and Jan, K.Y. NADH oxidase activation is involved in arsenite-induced oxidative DNA damage in human vascular smooth muscle cells. Circulation Research. 86(5): 514-519, 2000.

7. Kojda, G. and Harrison, D. Interactions between NO and reactive oxygen species: pathophysiological importance in atherosclerosis, hypertension, diabetes and heart failure. [Review] [100 refs] Cardiovascular Research. 43(3): 562-571, 1999.

9. Ibrahim, W., Lee, U.S., Yen, H.C., St Clair, D.K. and Chow, C.K. Antioxidant and oxidative status in tissues of manganese superoxide dismutase transgenic mice. Free Radical Biology & Medicine. 28(3): 397-402, 2000.