探討運動習慣、SUV39H1 rs3373單核苷酸多態性與BDNF啟動子甲基化的相關性研究

The association of exercise with SUV39H1 rs3373 polymorphism and BDNF promoter methylation in Taiwanese adults.

陸玟諭(Wen-Yu Lu)

指導教授 ： 廖勇柏

中山醫學大學/健康管理學院/公共衛生學系/碩士(2019年)

https://doi.org/10.6834/CSMU201900161

摘要

前言：
在臺灣使用抗憂鬱藥物的人數不斷上升，顯示有許多人飽受憂鬱情緒所苦，憂鬱症所造成的情緒障礙小至影響個人生活，大至對於醫療支出、經濟社會皆造成影響。2017年疾病造成負擔報告憂鬱症高居第三，而憂鬱症是造成自殺的主因，但就診率仍無法全面提升，使得在公共衛生疾病防治仍然是一大挑戰。腦源性神經營養因子(BDNF)在大腦中不可或缺，而其基因表達也與許多精神方面疾病有關，已經有文獻指出運動能提升BDNF含量，對於大腦運作產生良好助益；SUV39H1基因功能為製造異染色質，因能穩定染色體而廣為人知。許多研究指出運動可以改善生理及心理狀態，目前已知BDNF基因甲基化的降低與改善憂鬱情緒有關，即便有大鼠實驗提出運動與BDNF啟動子甲基化降低的相關，但在人體身上尚未得到驗證。因此，本研究目的為瞭解運動習慣、SUV39H1 rs3373基因型與BDNF啟動子甲基化之間的相關性。
研究方法：
本研究資料來自「臺灣人體生物資料庫(Taiwan Biobank)」，收集30至70歲具本國籍且未曾被診斷為癌症的成人，本研究納入771人(389位男性及382位女性)。利用多變量線性回歸(Multiple Linear Regression)探討運動習慣、rs3373基因型與BDNF啟動子甲基化相關，分析皆調整了性別、年齡、婚姻狀況、健康行為、飲食狀況、收入及BMI等變項。
結果：
運動習慣與rs3373基因型之間對於BDNF啟動子甲基化有交互作用(P-value=0.0107)。與rs3373基因型為GG相比，當基因型為AA時，BDNF基因甲基化程度顯著較低(β=-0.00307，P-value=0.0192)，GA基因型沒有達到顯著。但趨勢分析(P-trend)有達統計顯著，P-value為0.0152。與沒有運動的人相比，有運動的人有較低的BDNF啟動子甲基化(β=-0.00203, P-value=0.0089)。平均每月收入少於一萬BDNF啟動子甲基化程度顯著高於平均每月收入大於一萬者(β=0.00224，P-value=0.0271)。
進一步以運動分層後發現僅有在有運動且基因型為AA，BDNF啟動子甲基化會顯著較低(β=-0.00432，P-value=0.0243)，P-trend僅在有運動習慣組有達統計顯著，P-value為0.0106。設定虛擬變項後，以沒有運動、rs3373基因型為GG為參考組，有運動且基因型為GA或AA的人BDNF啟動子甲基化程度顯著較低，呈現劑量效應關係。
結論：
有運動習慣與BDNF啟動子甲基化較低相關，收入較低則與BDNF啟動子高甲基化相關。rs3373基因型為AA對於BDNF啟動子甲基化有保護作用，但若是沒有加上運動，即使本該為保護的基因型AA也無法發揮效果。由此可知，運動是與BDNF啟動子低甲基化相關的重要可改變因子。

關鍵字

BDNF啟動子甲基化 ； SUV39H1 ； rs3373 ； 運動 ； 憂鬱症 ； 臺灣人體生物資料庫

並列摘要

In recent years, there has been a surge in the use of antidepressants in Taiwan, revealing that many people suffer from depression. Mental disorders may cause disability in the basic activities of daily living, economic and social loss as well as an increase in medical expenditure. Depression is a challenging public health issue. It is reported as the third global disease burden and the main cause of suicide. The SUV39H1 gene functions mainly in the production of heterochromatin, which is well-known for stabilizing chromosomes. The administration of SUV39H1 inhibitor was found to be associated neuroprotection and upregulation. Even though exercise was associated with low BDNF methylation in rat models, this association has not been fully assessed in humans. Hence, the effect is in humans is still unknown. The aim of this study was to explore the association of exercise habits and rs3373 SUV39H1 polymorphism with BDNF promoter methylation.
Data were retrieved from the Taiwan Biobank, which collects data of Taiwanese adults aged 30 to 70 years without any personal history of cancer. A total of 771 participants comprising 389 men and 382 women were included in the study. Multiple linear regression was used to determine association of exercise habits and rs3373 polymorphism with BDNF promoter methylation. In all the analyses, adjustments were made for sex, age, marital status, health behavior, dietary habits, income and BMI, among others.
The interaction between exercise habits and rs3373 polymorphism was significant (P-value = 0.0107). With the GG genotype as the reference, BDNF promoter methylation levels were significantly lower in individuals with the AA genotype (β= -0.00307; P-value = 0.0192). However, there was no significant association in those with the GA genotype. Exercise was significantly associated with lower BDNF promoter methylation levels (β = -0.00203; P-value = 0.0089) compared with no exercise. Monthly income less than NTD 10,000 was associated with higher BDNF promoter methylation levels (β =0.00224; P-value = 0.0271).
After stratification by exercise habits, the AA genotype was significantly associated with lower BDNF promoter methylation levels in individuals who did exercise (β = -0.00432; P-value = 0.0243). However, there was no significant association between the GA genotype and BDNF promoter methylation in those who did exercise. Notwithstanding, a significant trend was observed (P-trend = 0.0106).
In conclusion, exercise was associated with lower BDNF promoter methylation levels, while lower income was associated with higher methylation levels. The BDNF promoter methylation levels were lower in individuals with the rs3373 AA genotype who did exercise. This means that the AA genotype might lower BDNF methylation, which might reduce the risk of depression. However, this protective effect might only be feasible among individuals who exercise. Therefore, exercise is necessary to improve mental health and people should be encouraged to maintain an active lifestyle.

並列關鍵字

BDNF promoter methylation ； SUV39H1 ； rs3373 ； exercise ； depression ； Taiwan Biobank

參考文獻

1. Hunter, D.J., Gene–environment interactions in human diseases. Nature Reviews Genetics, 2005. 6(4): p. 287.

2. Organization, W.H., Depression: let’s talk” says WHO, as depression tops list of causes of ill health. Saudi Med J, 2017. 38(5): p. 565.

3. Murray, C.J., A.D. Lopez, and W.H. Organization, The global burden of disease: a comprehensive assessment of mortality and disability from diseases, injuries, and risk factors in 1990 and projected to 2020: summary. 1996.

4. Findings from the Global Burden of Disease Study 2017. 2019; Available from: http://www.healthdata.org/policy-report/findings-global-burden-disease-study-2017.

5. World Health Organization-Depression. 2018; Available from: https://www.who.int/news-room/fact-sheets/detail/depression.