Abstract WE407: Causative Association Between Longer Leukocyte Telomere Length (LTL) and Higher Risk of Atrial Fibrillation: A Meta-analysis of Mendelian Randomization Studies

Background: Atrial Fibrillation(AF) is one of the most common cardiac arrhythmias and advancing age has been associated with increased incidence of AF. Leukocyte Telomere length (LTL) has been implicated with cardiovascular aging, but its causal association with AF and its magnitude remains to be studied. This meta-analysis aims to determine the causal association between LTL and the risk of AF using Mendelian Randomization (MR) studies. Methods: A systematic search of literature was done in PubMed, Scopus and Google Scholar for MR studies addressing the causal relation between LTL and risk of AF. Studies published upto May 2025 were screened adhering to the PRISMA guidelines. Screening and data extraction was done by 2 independent authors to assess the quality of eligible studies. Data was extracted from 4 eligible studies and methods such as inverse- variance weighted (IVW), Weighted Median Approach and MR-Egger were used to pool causal estimates. Studies were analyzed qualitatively due to underlying methodological heterogeneity and potential sources of bias were evaluated through sensitivity analyses reported in the studies. Results: Four MR studies using multiple GWAS databases explored whether LTL had a causal impact on the risk of AF. One study reported that longer LTL was significantly associated with an increased risk of AF with OR of 1.083 (95% Cl 1.009-1.164, p = 0.026) in the UK Biobank and 1.182 (95% Cl 1.039-1.344, p = 0.011) in the Finngen dataset. In contrast, three other studies found no significant causal effect of LTL on AF. A meta- analysis of these studies yielded a pooled OR of 1.08 (95% Cl, 1.01-1.16, p = 0.02), with moderate heterogeneity (I 2 =60.7%, p=0.04), suggesting a statistically significant association between longer LTL and increased AF risk. A bidirectional analysis offered a unifocal perspective, suggesting that AF may actually lead to telomere shortening, with an OR of 0.989 (95% Cl: 0.981-0.997, p = 0.007). Additional observations included associations between longer LTL and increased left ventricular volume, as well as potential protective effects of LTL against other cardiovascular diseases. Conclusion: This meta-analysis suggests a statistically significant association between longer LTL and an 8% increased odds of AF. However, these findings are also specific to the European population, underscoring the need for future MR studies in different populations to enhance generalizability.