- 學位論文
孟德爾隨機化探非脂肪體重指標與心房顫動之因果關係
Association of Fat-Free Mass Indices and Atrial Fibrillation: Mendelian Randomization Analysis
摘要
研究背景：流行病學研究表明，肥胖與心房顫動有所相關，並且已證實具有因果關係。從臨床觀察，體型的增加亦可能會增加心房顫動的風險，且與肥胖無關。而身體質量（body mass）及身體質量指數（body mass index, BMI）並非合適的人體測量指標，因其無法區分非脂肪質量和脂肪質量。本研究採用和軀幹非脂肪體重（trunk fat-free mass）與非脂肪體重指標（fat-free mass index）相關的單核苷酸多態性（SNP）為工具變項，執行孟德爾隨機化，藉此推論身形和心房顫動的因果關係。 材料與方法：使用英國生物資料庫（UK Biobank），共納入了7,350名受試者，包括1,225（16.67％）名心房顫動病例以及6,125名（83.33％）非心房顫動對照組。為了揭示軀幹非脂肪體重及非脂肪體重指標與心房顫動之間的因果關係，執行孟德爾隨機化。並使用逆方差加權法於英國生物資料庫(UK Biobank)進行因果估計。輔以加權中位數方法、MR-Egger迴歸和孟德爾隨機多效性殘差和離群值（MR-PRESSO）全局檢驗來檢測水平多效性效應。 結果：孟德爾隨機分配分析揭示非脂肪體重指標（β_IVW=0.202, p=8.42Ε-04）與軀幹非脂肪體重（β_IVW=0.169, p=1.53Ε-04）對心房顫動具有因果關係。顯示隨著非脂肪體重增加，對於罹患心房顫動之風險有正向且統計上顯著的因果關係。 結論：非脂肪體重指標及軀幹非脂肪體重與心房顫動之間存在強而一致的正相關，以孟德爾隨機分配分析表明非脂肪體重與心房顫動有因果關係。本研究亦使用多基因風險評分（polygenic risk score）作為工具變量，亦表明非脂肪體重指標和軀幹非脂肪體重對心房顫動的因果作用。與傳統的孟德爾隨機分配分析一致。
並列摘要
Background: Various epidemiological studies have proven that obesity increases the risk of atrial fibrillation (AFib), increased body size can also have similar effects, independent of obesity. Nevertheless, BMI and body mass are not suitable body composition indices for anthropometric aspects, as it cannot distinguish between fat-free mass (muscle and skeleton mass) and fat mass. The main purpose of this study is to uncover the potential causation of the fat-free mass index (FFMI) and trunk fat-free mass (TFFM) in AFib progression by use of single nucleotide polymorphism (SNPs) as instruments (IVs) that are obtained from UK Biobank (UKB). Methods and Materials: A total of 7,350 subjects, comprising of 1,225 (16.67%) AFib cases and 6,125 (83.33%) non-AFib controls, were included in this study from the UKB. To reveal the causal relationship between body composition and AFib, MR was implemented. The causal estimates between all SNPs and exposure of interests were evaluated using an inverse-variance weighted method in UKB. Weighted median method, MR-Egger regression, and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR- PRESSO) global test to detect horizontal pleiotropy effects which violate the exclusion restriction assumption in the sensitivity analysis. Results: We revealed the causal roles of the FFMI and TFFM for AFib. Using the inverse-variance weighted method supported the evidence that the causal relationship between FFMI on AFib was significantly positive (β_IVW=0.202, p=8.42Ε-04). Furthermore, statistical evidence for the positive causal relationship of raised TFFM with AFib risk (β_IVW=0.169, p=1.53Ε-04) was found which implied that as TFFM increased. Conclusion: This MR analysis suggested that fat-free mass is causally related to AFib, and a novel finding is a strong and consistent positive association between genetically predicted FFMI, TFFM and AFib. We have also provided PRS as an instrument variable for revealing the causal roles of the FFMI and TFFM for AFib, and the result is consistent with traditional MR analysis (using multiple SNPs as IVs).