Shared genetic etiology between chronic diseases and heart failure risk: the dual role of leukocyte telomere length

Introduction Genetic susceptibility to various chronic diseases has been shown to influence heart failure (HF) risk. However, the pathogenic mechanisms underlying these associations, particularly the role of phenotypic leukocyte telomere length (LTL), is unknown. We investigated the shared genetic etiology between chronic diseases, various traits, and HF risk, and whether LTL mediates or modifies these relationships. Methods We conducted prospective cohort analyses on 404,883 European participants from the UK Biobank, including 9,989 incident HF cases. Multivariable Cox regression was used to estimate associations between HF risk and 24 polygenic risk scores (PRSs) for various diseases or traits previously generated in the UK Biobank using a Bayesian approach. We assessed multiplicative interactions between the PRSs and LTL previously measured in the UK Biobank using quantitative PCR. Mediation analyses were conducted to estimate the proportion of the total effect of PRSs acting indirectly through LTL, an integrative marker of biological aging. Results We identified 9 PRSs associated with HF risk, including those for various cardiovascular diseases or traits, rheumatoid arthritis (P=1.3E-04), and asthma (P=1.8E-08). Additionally, longer LTL was strongly associated with decreased HF risk (P-trend=1.7E-08). Notably, the asthma PRS had a super-multiplicative interaction with LTL (P-interaction=2.8E-03). However, LTL mediated only 1.13% (P<0.001) of the total effect of the asthma PRS on HF risk. Conclusions Our findings shed light onto the shared genetic etiology between HF risk, asthma, rheumatoid arthritis, and other traits. Longer LTL strengthened the genetic effect of asthma on HF, supporting their utility in risk stratification analyses. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported by intramural funding from the National Cancer Institute and National Heart, Lung, and Blood Institute. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Data used for this study are publicly available at: I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data used for this study are publicly available at: Meta-data and codes produced in the present study are available upon reasonable request to the authors.