Elucidating the role of leukocyte telomere length in the risk of atrial fibrillation

Abstract Background Atrial fibrillation (AF) is strongly associated with older age. However, it is unclear whether, in addition to chronological age, more advanced biological ageing confers AF risk. Previous studies suggest AF and peripheral leukocyte telomere length (LTL, a measure of biological ageing) are associated, but this relationship and the causal relevance remains controversial. Purpose This study aims to explore the role of LTL in risk of AF through observational analyses and Mendelian randomisation (MR). Methods UK Biobank (UKB) is a large prospective study of individuals 40 to 69 years of age in which 393,018 participants have measured LTL and genetic data available. Observational associations between LTL and incident AF (ascertained in hospital admission data) were estimated using Cox proportional hazards models adjusted for potential confounders (age at LTL measurement, body mass index, physical activity, smoking status, alcohol intake, ethnicity, Townsend deprivation index, and sex). MR analyses included 195 SNPS previously shown to have conditionally independent genome-wide significant associations with measured LTL. In UKB, causal effects of genetically-predicted LTL for AF risk were estimated using the inverse-variance weighted approach. Validation was undertaken in independent data from the AFGen Consortium (Nielsen et al. 2015). Sensitivity analyses to consider the potential effects of pleiotropy were also conducted (weighted median MR, MR-Egger and Radial MR). Results Among 385,851 participants with available LTL measurements and without AF at baseline, 26,639 (6.9%) developed AF during follow-up. Longer measured LTL was associated with lower risk of AF (HR=0.98, 95%CI=0.97-0.99, p=0.002), with the cumulative incidence of AF by LTL quartile shown in Figure 1. However, MR analyses did not support a causal association between genetically-predicted LTL and AF (OR=1.04, 95%CI=0.96-1.14, p=0.36). Sensitivity analyses were consistent with the primary MR results, and did not suggest unbalanced pleiotropy (MR Egger intercept, p=0.54). Radial MR identified 4 outlier SNPs (associated with height, adiposity, and blood cell traits) but results remained consistent after exclusion of these variants (OR 1.00, 95%CI 0.93-1.08, p=0.90). Validation analyses in independent data were consistent with the non-significant association observed in UKB (OR=1.08, 95%CI=0.99-1.18, p=0.07; Figure 2). Conclusion This study combines conventional and genetic epidemiological approaches to explore the role of LTL in risk of AF. Large-scale observational analyses in UKB suggest an inverse association between LTL and AF. However, despite previous studies reporting associations between genetically-determined LTL and AF risk factors, our validated MR results do not support a causal relationship between LTL and AF, and potentially suggest observational associations are due to residual confounding.Figure 1Figure 2