Yi-He Chen

To date, effective preventive and therapeutic strategies for early-stage bradyarrhythmia remain limited. We first calculated two well-established biological aging (BA) measures (Klemera-Doubal Method [KDM] and Phenotypic Age [PhenoAge]), with BA acceleration defined as the residual from regressing each BA measure on chronological age. Cox proportional hazards models were used to evaluate the effects of BA acceleration on bradyarrhythmia risk. We then conducted epigenetic Mendelian randomization (MR) and colocalization analyses to prioritize aging-related DNA methylation CpG sites for bradyarrhythmias. In the UK Biobank cohort of 298,214 individuals, per 1-SD increase in PhenoAge acceleration and KDM-BA acceleration were significantly associated with a 13% (HR = 1.13, 95% CI 1.11-1.15, P < 0.001) and 11% (HR = 1.11, 95% CI 1.09-1.13, P < 0.001) higher incidence of bradyarrhythmia. Epigenetic MR and colocalization analyses suggested that cg11410859 (SCN5A), cg18249173 (TBX20), cg07185587 (AKAP6), cg16555537 (TRIP6), cg10459018, cg03473532 (MKLN1), and cg13654588 (PRLHR) were associated with a reduced risk of bradyarrhythmias, whereas cg25286333 (RNF207) and cg02447380 (RAB42) were associated with an increased risk of bradyarrhythmias. In summary, our study elucidated the role of accelerated biological aging and underlying epigenetic modifications in bradyarrhythmia, providing novel insights into its prevention and treatment.

The relationships among obesity, accelerated biological aging, and asthma, as well as the underlying epigenetic mechanisms, remain incompletely understood. We conducted a prospective cohort study in the UK Biobank to evaluate whether accelerated biological aging mediates the association between obesity and incident asthma. We then performed two-sample Mendelian randomization (MR) to assess the potential causal effect of accelerated biological aging on asthma from an epigenetic perspective. Epigenetic MR and colocalization analyses were used to prioritize aging-related DNA methylation (DNAm) CpG sites associated with asthma. Finally, single-cell RNA sequencing (scRNA-seq) was applied to characterize the cell-type-specific expression patterns of CpG-mapped genes. In the UK Biobank cohort, KDM-BA acceleration and PhenoAge acceleration partially mediated the association between obesity and asthma, with proportions mediated of 4.0% and 12.2%, respectively. Two-sample MR further suggested that DNAm PhenoAge acceleration was associated with a higher risk of asthma (OR = 1.02; 95% CI: 1.01-1.03; P = 0.004). Epigenetic MR and colocalization analyses suggested that cg02010481 (JAZF1), cg17929770 (RSPH6A), cg19927816 (SYMPK; RSPH6A), cg08544331 (RUNX3), cg15498134 (RUNX3), and cg04389704 (FBXL19) were associated with a reduced risk of asthma, whereas cg16553500 (COL16A1), cg16351569, cg10036013 (FOXK1), cg11647481 (FOXK1), cg23776012 (KRT222), and cg08258403 were associated with an increased risk of asthma. In scRNA-seq analyses, JAZF1, SYMPK, FOXK1, and RUNX3 were differentially expressed across multiple immune cell types. This study demonstrates that accelerated biological aging partially mediates the association of obesity with asthma and further elucidates underlying epigenetic mechanisms linking aging to asthma.

To date, there is still a lack of studies focusing on the interactions between tobacco smoking, epigenetic modifications, and heart failure (HF) risk. We f

Background: Cardiac arrhythmias pose a major health concern while the role of antidiabetic medications in cardiac arrhythmic risks is not fully understood. Method: We conducted a two‐sample Mendelian Randomization (MR) analysis using genetic instruments extracted from hemoglobin A1C (HbA1c) as proxies for antidiabetic drug targets to evaluate their causal relationship with five cardiac arrhythmias derived from the Finngen database. Summary‐data‐based Mendelian randomization (SMR) utilizing gene expression data from the eQTLgen consortium was further employed to assess the role of antidiabetic drug targets in cardiac arrhythmias from the gene expression perspective. Results: Three significant associations were identified. Sulfonylurea targets KCNJ11/ABCC8 were associated with a decreased incidence of paroxysmal tachycardia (OR: 0.69, 95% CI: 0.56, 0.86, P _FDR = 0.022). Sodium‐glucose cotransporter 2 inhibitor (SGLT2i) target SLC5A2 was linked to a reduced risk of right bundle branch block (OR: 0.85, 95% CI: 0.77, 0.94, PFDR = 0.022), and thiazolidinediones (TZDs) targeting RXRB were associated with a lowered atrial fibrillation occurrence (OR: 0.88, 95% CI: 0.82, 0.94, P _FDR = 0.019). No significant relationships were found between any antidiabetic drug targets and left bundle branch block or atrioventricular block. SMR analysis indicated that lowered expression of KCNJ11 was related to a decreased paroxysmal tachycardia risk (OR: 1.05, 95% CI: 1.01, 1.08, P _SMR = 0.010), further confirming the role of KCNJ11 in paroxysmal tachycardia. Conclusion: Our findings suggest that several antidiabetic drug targets may have potential therapeutic applications in the management of cardiac arrhythmias.