Chen Ying, Li Bingxun, Xu Hongxuan, Wu Lin
Department of Cardiology, Peking University First Hospital, Beijing, China.
Key Laboratory of Medical Electrophysiology of the Ministry of Education and Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China.
Front Pharmacol. 2024 Jul 29;15:1439816. doi: 10.3389/fphar.2024.1439816. eCollection 2024.
Mitochondrial dysfunction is one of the important patho-mechanisms in the development of atrial fibrillation (AF) with underidentified genetic pathophysiology. Summarized data of methylation, expression and protein abundance levels of mitochondria-related genes were obtained from corresponding studies, respectively. Genes related to mitochondria dysfunction in associations with AF were obtained from the UK Biobank (discovery), and the FinnGen study (replication). Summary-data-based Mendelian randomization analysis (SMR) was performed to assess potential causal relationships between mitochondria-related genes related to the molecular features of AF. Colocalization analysis was further conducted to assess whether the identified signal pairs shared causal genetic variants. Five mitochondria-related genes were found to have causal effects with AF in the sensitivity and the colocalization analyses. Strong associations with increased risk of AF were identified with increased expression level of 4 mitochondria-related genes, including PCCB (OR 1.09, 95% CI 1.05-1.12; PPH4 = 0.95), COX18 (OR 1.83, 95% CI 1.29-2.60; PPH4 = 0.83), SLC25A15 (OR 1.34, 95% CI 1.14-1.58; PPH4 = 0.85), and STX17 (OR 1.16, 95% CI 1.08-1.24; PPH4 = 0.76). Conversely, genetically predicted higher levels expression of UQCC1 (OR 0.94, 95% CI 0.91-0.97) were associated with decreased risk of AF. After further tissue-specific validation, genetically predicted expression levels of PCCB (OR 1.12, 95%, CI 1.01-1.24, = 0.025) and STX17 (OR 1.13, 95%, CI 1.04-1.23, = 0.006) in atrial appendage were strongly associated with the increased risk of AF. Mitochondria-related genes are involved either positively (PCCB, COX18, SLC25A15 and STX17) or negatively (UQCCI) in the pathogenesis and the development of AF. These candidate genes may serve as targets for potential development of agents in the prevention and treatment of AF.
线粒体功能障碍是心房颤动（AF）发生发展过程中的重要病理机制之一，其遗传病理生理学尚不明确。分别从相应研究中获取线粒体相关基因的甲基化、表达及蛋白质丰度水平的汇总数据。与AF相关的线粒体功能障碍相关基因来自英国生物银行（发现队列）和芬兰基因研究（验证队列）。进行基于汇总数据的孟德尔随机化分析（SMR），以评估与AF分子特征相关的线粒体相关基因之间的潜在因果关系。进一步进行共定位分析，以评估所识别的信号对是否共享因果遗传变异。在敏感性分析和共定位分析中，发现5个线粒体相关基因与AF存在因果效应。4个线粒体相关基因表达水平升高与AF风险增加显著相关，包括PCCB（比值比1.09，95%置信区间1.05 - 1.12；PPH4 = 0.95）、COX18（比值比1.83，95%置信区间1.29 - 2.60；PPH4 = 0.83）、SLC25A15（比值比1.34，95%置信区间1.14 - 1.58；PPH4 = 0.85）和STX17（比值比1.16，95%置信区间1.08 - 1.24；PPH4 = 0.76）。相反，基因预测的UQCC1较高表达水平（比值比0.94，95%置信区间0.91 - 0.97）与AF风险降低相关。经过进一步的组织特异性验证，基因预测的心耳中PCCB（比值比1.12，95%，置信区间1.01 - 1.24，P = 0.025）和STX17（比值比1.13，95%，置信区间/1.04 - 1.23，P = 0.006）的表达水平与AF风险增加密切相关。线粒体相关基因在AF的发病机制和发展过程中起正向（PCCB、COX18、SLC25A15和STX17）或负向（UQCCI）作用。这些候选基因可能成为预防和治疗AF潜在药物开发的靶点。
