楊浩然Yang, Hao-Jan廖勇柏Liaw, Yung-Po楊登琦YANG,TENG-CHIYANG公共衛生學系博士班2026-02-102030-07-2520252025-07-18https://handle.ncl.edu.tw/11296/328nk6https://scholars.csmu.edu.tw/handle/123456789/5345背景與目標：慢性代謝性疾病如糖尿病，其發生與基因、環境及生活型態因素交互作用密切相關。FK506结合蛋白5(FK506 binding protein 5，FKBP5)基因為壓力反應相關基因，參與糖皮質激素受體調控，近年來已被證實與代謝功能、免疫調節及胰島素敏感性相關。FKBP5基因DNA甲基化(FKBP5 gene DNA methylation)變化，尤其是特定CpG位點(cytosine-phosphate-guanine sites，CpG sites)的甲基化異常，與多種慢性疾病如糖尿病、憂鬱症、心血管疾病及老化相關聯。運動則被認為是可透過表觀遺傳機制改善代謝功能的非藥物性介入手段。本研究目的是探討性別、糖尿病及運動間交互作用對FKBP5基因兩個關鍵CpG位點(cg22363520與cg00862770)甲基化表現的綜合影響，並探討其作為表觀遺傳生物標記之潛力。方法：本研究使用臺灣人體生物資料庫(Taiwan Biobank)中 1,103位年齡介於30至70歲之受試者資料，包含人口學變項、生活型態、疾病狀態資料與 DNA甲基化資訊。採用 Illumina Infinium® MethylationEPIC BeadChip陣列檢測血液樣本中FKBP5基因的甲基化程度，並擷取 FKBP5基因中兩個具文獻支持的CpG位點進行分析。生活型態資訊來自問卷，包括運動頻率與糖尿病診斷情形。以多元線性迴歸分析性別、糖尿病與運動對cg22363520與cg00862770甲基化β值的交互作用，並進行性別分層分析，以探討不同群體間甲基化程度的變化趨勢。結果：結果顯示，在CpG位點cg22363520，規律運動與非糖尿病狀態間具交互作用(β = -0.00195，p = 0.0157)，顯著降低非糖尿病男性的甲基化程度；在cg00862770位點，則於糖尿病參與者中觀察到運動顯著降低甲基化程度(β = -0.00611，p = 0.0081)。此外，在有運動習慣者中，糖尿病顯著影響cg22363520位點(p = 0.0241)，而在無運動習慣者中，糖尿病顯著影響cg00862770位點(p = 0.0076)。性別分析亦顯示，cg00862770位點呈現男性高於女性的甲基化差異。整體結果顯示FKBP5基因甲基化在性別、糖尿病狀態與運動間呈現複雜交互效應，具位點特異性。結論：本研究結果發現，FKBP5基因甲基化受到性別、糖尿病與運動的交互影響，並具位點特異性。運動可能透過調節FKBP5特定位點的甲基化狀態，改善壓力反應與代謝功能。cg22363520與cg00862770位點可望作為糖尿病風險評估與運動干預效益評估之潛在生物標記。此研究強調了表觀遺傳在疾病預防與個體化健康促進策略中的重要角色。Background and Objective: Chronic metabolic diseases such as type 2 diabetes mellitus (T2DM) result from complex interactions among genetic, environmental, and lifestyle factors. FKBP5 (FK506 binding protein 5) gene is a glucocorticoid-regulating gene involved in stress response, immune regulation, and metabolic function. Aberrant DNA methylation of FKBP5—particularly at CpG sites—has been linked to insulin resistance, cardiovascular disease, aging, and psychiatric conditions. Exercise has emerged as a non-pharmacological intervention that can modulate gene expression via epigenetic modifications, including DNA methylation.The aim of this study is to investigate the combined effects of the interaction between gender, diabetes, and physical activity on the methylation status of two key CpG sites (cg22363520 and cg00862770) within the FKBP5 gene, and to explore their potential as epigenetic biomarkers.Methods: This study utilized data from 1,103 participants aged 30 to 70 from the Taiwan Biobank, including demographic variables, lifestyle information, medical history, and DNA methylation profiles. Methylation levels of the FKBP5 gene in blood samples were measured using the Illumina Infinium® MethylationEPIC BeadChip array, focusing on two CpG sites previously supported by the literature. Lifestyle data, including exercise frequency and diabetes diagnosis, were obtained through questionnaires.Use multiple linear regression analysis to examine the interaction effects of gender, diabetes, and physical activity on the methylation β-values of cg22363520 and cg00862770, and conduct gender-stratified analyses to explore trends in methylation level changes across different groups.Results: The results showed an interaction between regular physical activity and non-diabetic status at the CpG site cg22363520 (β = -0.00195, p = 0.0157), with a significant decrease in methylation levels observed among non-diabetic males. At cg00862770, exercise was associated with a significant reduction in methylation levels among participants with diabetes (β = -0.00611, p = 0.0081). Furthermore, among individuals who engaged in regular physical activity, diabetes significantly affected methylation at cg22363520 (p = 0.0241), while among those without exercise habits, diabetes significantly influenced methylation at cg00862770 (p = 0.0076). A sex-based analysis also revealed higher methylation levels at cg00862770 in males compared to females. Overall, the findings indicate that methylation of the FKBP5 gene is subject to complex, site-specific interactions involving sex, diabetes status, and physical activity.Conclusion: This study found that FKBP5 gene methylation is influenced by the interplay of sex, diabetes, and physical activity, and that this effect is site-specific. Exercise may help improve stress response and metabolic function by modulating the methylation status of specific FKBP5 loci. The CpG sites cg22363520 and cg00862770 show potential as biomarkers for assessing diabetes risk and the benefits of exercise intervention. These findings underscore the important role of epigenetics in disease prevention and personalized health promotion strategies.性別糖尿病運動FKBP5基因DNA甲基化GenderDiabetesExerciseFKBP5 GeneDNA Methylationthesis