Association between epigenetic aging and atrioventricular block: a two-sample Mendelian randomization study

Atrioventricular block (AVB) is a prevalent bradyarrhythmia. This study aims to investigate the causal effects of epigenetic aging, as inferred from DNA methylation profiles on the prevalence of AVB by Mendelian randomization (MR) analysis. Genetic instruments for epigenetic aging and AVB were obtained from genome-wide association study data in the Edinburgh DataShare and FinnGen biobanks. Univariable and multivariable MR analyses were conducted to evaluate causal associations. Additionally, we employed sensitivity tests to assess the robustness of the MR findings. MR analysis showed that genetically predicted GrimAge acceleration was significantly associated with a higher risk of AVB (inverse variance-weighted: <i>p</i> = 0.010, 95% confidence interval (CI) = 1.024–1.196; weighted median: <i>p</i> = 0.031, 95% CI = 1.009–1.215). However, no evidence supported a causal relationship between AVB and epigenetic aging. The association between epigenetic aging and AVB was established using multivariate MR analysis after adjusting for various risk factors. Sensitivity analyses confirmed the reliability and robustness of the results. Our findings suggest that epigenetic aging in GrimAge may increase the risk of AVB, emphasizing the importance of addressing epigenetic aging in strategies for AVB prevention. Atrioventricular block (AVB) is a heart problem that makes the heart beat too slowly. This can cause serious health problems. Getting older is one cause, but scientists are also studying ”biological aging.” This means how the body ages based on changes in genes, not just how many years a person has lived. We looked at different ways to measure biological aging. One measure called GrimAge, showed that people who age faster have a higher chance of getting AVB. Slowing down biological aging, mainly GrimAge, might help keeping from AVB.

房室传导阻滞（Atrioventricular block, AVB）是一种常见的缓慢性心律失常。本研究旨在通过孟德尔随机化（Mendelian randomization, MR）分析，基于DNA甲基化谱推断的表观遗传衰老，探究其与房室传导阻滞患病率的因果效应。研究从爱丁堡数据共享平台（Edinburgh DataShare）与芬兰基因生物样本库（FinnGen biobanks）的全基因组关联研究数据中，获取了表观遗传衰老与房室传导阻滞的遗传工具变量。随后开展单变量与多变量孟德尔随机化分析，以评估二者的因果关联；同时辅以敏感性检验，以验证孟德尔随机化研究结果的稳健性。孟德尔随机化分析显示，遗传预测的GrimAge加速与更高的房室传导阻滞风险显著相关（逆方差加权法：p=0.010，95%置信区间（confidence interval, CI）=1.024~1.196；加权中位数法：p=0.031，95%CI=1.009~1.215）。然而，未发现房室传导阻滞与表观遗传衰老存在因果关联的证据。在校正多种危险因素后，多变量孟德尔随机化分析证实了表观遗传衰老与房室传导阻滞的关联。敏感性分析进一步验证了本研究结果的可靠性与稳健性。本研究结果表明，GrimAge所表征的表观遗传衰老可能会增加房室传导阻滞的发病风险，提示在房室传导阻滞的预防策略中，针对表观遗传衰老的干预具有重要价值。房室传导阻滞（AVB）是一种会导致心脏搏动过缓的心脏疾病，可引发严重的健康问题。年龄增长是其致病因素之一，但科学家们也在研究“生物衰老”——即基于基因层面变化的机体衰老进程，而非仅以实际生存年限衡量的衰老。我们分析了多种生物衰老的评估方式，其中名为GrimAge的评估指标显示，衰老速度更快的人群罹患房室传导阻滞的风险更高。延缓生物衰老（尤其是GrimAge所表征的衰老进程）或有助于预防房室传导阻滞的发生。