Qiu Baizhi, Wen Shuyang, Li Zifan, Cai Yuxin, Zhang Qi, Zeng Yuting, Zheng Shuqi, Lin Zhishan, Xiao Yupeng, Zou Jihua, Huang Guozhi, Zeng Qing
Department of Rehabilitation Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
School of Nursing, Southern Medical University, Guangzhou, China.
Brain Behav. 2025 Mar;15(3):e70412. doi: 10.1002/brb3.70412.
Emerging evidence from observational studies suggested that epigenetic age acceleration may result in an increased incidence of stroke and poorer functional outcomes after a stroke. However, the causality of these associations remains controversial and may be confounded by bias. We aimed to investigate the causal effects of epigenetic age on stroke and its functional outcomes.
We conducted a two-sample Mendelian randomization (MR) analysis to explore the causal relationships between epigenetic age and stroke and its outcomes. Additionally, a two-step MR analysis was performed to investigate whether lifestyle factors affect stroke via epigenetic age. Datasets of epigenetic age were obtained from a recent meta-analysis (n = 34,710), while those of stroke and its outcomes were sourced from the MEGASTROKE (n = 520,000) consortium and Genetics of Ischaemic Stroke Functional Outcome (GISCOME) network (n = 6165).
Two-sample MR analysis revealed a causal relationship between PhenoAge and small vessel stroke (SVS) (OR = 1.07; 95% CI, 1.03-1.12; p = 2.01 × 10). Mediation analysis through two-step MR indicated that the increased risk of SVS due to smoking initiation was partially mediated by PhenoAge, with a mediation proportion of 9.5% (95% CI, 1.6%-20.6%). No causal relationships were identified between epigenetic age and stroke outcomes.
Our study supports using epigenetic age as a biomarker to predict stroke occurrence. Interventions specifically aimed at decelerating epigenetic aging, such as specific lifestyle changes, offer effective strategies for reducing stroke risk.
观察性研究的新证据表明，表观遗传年龄加速可能导致中风发病率增加以及中风后功能预后较差。然而，这些关联的因果关系仍存在争议，可能会受到偏差的混淆。我们旨在研究表观遗传年龄对中风及其功能预后的因果效应。
我们进行了一项两样本孟德尔随机化（MR）分析，以探讨表观遗传年龄与中风及其预后之间的因果关系。此外，还进行了两步MR分析，以研究生活方式因素是否通过表观遗传年龄影响中风。表观遗传年龄数据集来自最近的一项荟萃分析（n = 34,710），而中风及其预后的数据集则来自MEGASTROKE（n = 520,000）联盟和缺血性中风功能预后遗传学（GISCOME）网络（n = 6165）。
两样本MR分析揭示了PhenoAge与小血管中风（SVS）之间的因果关系（OR = 1.07；9５％CI，1.03-1.12；p = 2.01×10）。通过两步MR进行的中介分析表明，开始吸烟导致SVS风险增加部分由PhenoAge介导，中介比例为9.5％（95％CI，1.6％-20.6％）。未发现表观遗传年龄与中风预后之间存在因果关系。
我们的研究支持将表观遗传年龄用作预测中风发生的生物标志物。专门针对减缓表观遗传衰老的干预措施，如特定的生活方式改变，为降低中风风险提供了有效的策略。
