Causal relationship between atrial fibrillation and leukocyte telomere length: A two sample, bidirectional Mendelian randomization study

BACKGROUND: Atrial fibrillation (AF) is an age-related disease, while telomeres play a central role in aging. But the relationship between AF and telomere length (LTL) is still controversial. This study aims to examine the potential causal association between AF and LTL by using Mendelian randomization (MR). METHODS: Bidirectional two-sample MR, expression and protein quantitative trait loci (eQTL and pQTL)-based MR were performed using genetic variants from United Kingdom Biobank, FinnGen, and a meta-analysis study, which comprised nearly 1 million participants in the Atrial Fibrillation Study and 470,000 participants in the Telomere Length Study. Apart from the inverse variance weighted (IVW) approach as the main MR analysis, complementary analysis approaches and sensitivity analysis were applied. RESULTS: The forward MR revealed a significant causal estimate for the genetically predicted AF with LTL shortening [IVW: odds ratio (OR) = 0.989, p = 0.007; eQTL-IVW: OR = 0.988, p = 0.005; pQTL-IVW: OR = 0.975, p < 0.005]. But in the reverse MR analysis, genetically predicted LTL has no significant correlation with AF (IVW: OR = 0.995, p = 0.916; eQTL-IVW: OR = 0.999, p = 0.995; pQTL-IVW: OR = 1.055, p = 0.570). The FinnGen replication data yielded similar findings. Sensitivity analysis ensured the stability of the results. CONCLUSION: The presence of AF leads to LTL shortening rather than the other way around. Aggressive intervention for AF may delay the telomere attrition.