Background: Chronic respiratory diseases (CRD) and cardiovascular diseases (CVD) are leading global health burdens. Despite being common, CRD and CVD comorbidity is often underestimated due to overlapping symptoms and risk factors. Consequently, their relationship remains unclear. Aims and Objectives: To determine the bidirectional genetic relationship between CRD and CVD and explore smoking and inflammation as potentially shared joint risk factors. Methods: We conducted bidirectional Mendelian randomization (MR) to explore CRD–CVD relationships. Summary statistics from genome-wide association studies were retrieved for COPD, asthma, coronary artery disease (CAD), myocardial infarction (MI), heart failure (HF), atrial fibrillation (AF), and ischemic stroke (IS). We performed additional analysis including univariable MR for smoking, multivariable MR adjusting for smoking, and cis–MR to investigate the role of inflammatory markers. Results: Our MR analysis found limited genetic evidence of relationships between CRD toward CVD, and vice versa. However, a nominally significant genetic association was observed between asthma and an increased risk of AF (ORIVW 1.036, 95% CI: 1.003–1.070), remaining weakly significant after adjusting for smoking (ORIVW 1.040, 95%CI 1.008–1.074). Genetically predicted lifetime smoking strongly increased all CRD and CVD risk. Additionally, genetically proxied IL6R concentration associated with increased asthma risk and decreased CAD, MI, AF, and IS risk, while IL1RN decreased COPD risk but increased CAD and MI risk. Conclusion: While we found limited genetic evidence linking CRD and CVD, smoking and inflammatory markers commonly affect both. These findings highlight the complexity of CRD-CVD comorbidities, whose pathophysiology likely does not involve direct causation of each other.

The authors have declared no competing interest.

The authors gratefully acknowledge the United Kingdom Research and Innovation Medical Research Council grants MR/W029790/1 (V.Z.). This research was supported by the UK Dementia Research Institute (V.Z.), which receives its funding from UK DRI Ltd, funded by the UK MRC, Alzheimer's Society and Alzheimer's Research UK.

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Most of the genome-wide association study (GWAS) data utilized in this research were openly available through the EBI GWAS Catalog before the study began. These datasets can be accessed at https://www.ebi.ac.uk/gwas/ Other data sources include: https://doi.org/10.5523/bris.10i96zb8gm0j81yz0q6ztei23d https://doi.org/10.1016/j.ebiom.2024.104991

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All data produced in the present study are available upon reasonable request to the authors.