A NEW Mendelian randomisation study suggests that chronic respiratory diseases (CRDs) and cardiovascular diseases (CVDs) comorbidity is largely driven by shared risk factors such as smoking and inflammation rather than direct genetic causation.
Respiratory and Cardiovascular Diseases Under Genetic Scrutiny
CRDs and CVDs represent two of the world’s most significant health burdens, yet their clinical overlap remains poorly understood due to similar symptoms and shared environmental risks. Historically, comorbidity has been assumed to reflect a direct causal link between disease groups, but evidence has been inconsistent. This study sought to clarify the relationship by analysing genetic determinants of CRD–CVD comorbidity, with a particular focus on smoking behaviour and inflammatory pathways that may influence both conditions.
Genetic Analysis Explores Shared Pathways
Researchers conducted bidirectional Mendelian randomisation using large genome-wide association datasets spanning COPD, asthma, coronary artery disease, myocardial infarction, heart failure, atrial fibrillation and ischaemic stroke. Follow-up analyses included models adjusting for lifetime smoking exposure and targeted evaluations of inflammatory markers via cis-MR approaches. This design allowed investigators to distinguish correlation from causation and isolate pathways that influence both respiratory and cardiovascular traits.
Findings Point to Risk Factors, Not Direct Causation
The study found limited evidence for a direct genetic connection between CRD and CVD, with most associations falling short of significance. A weak but nominal genetic link emerged between asthma and increased atrial fibrillation risk, persisting after adjustment for smoking (odds ratio inverse-variance weighted:1.040, 95% CI 1.008–1.074). In contrast, genetically predicted lifetime smoking strongly elevated the risk of every CRD and CVD examined, underscoring its dominant role in multimorbidity. Inflammatory markers also showed divergent influences: higher IL6R concentrations increased asthma risk while reducing several CVD risks, whereas IL1RN lowered COPD risk but increased CAD and MI susceptibility. These patterns suggest complex, pathway-specific interactions rather than a unifying causal mechanism behind CRD–CVD comorbidity.
Conclusion
The findings indicate that CRD–CVD comorbidity is unlikely to arise from direct genetic causation, instead reflecting shared behavioural and inflammatory drivers. Understanding these pathways may improve prevention strategies across both disease groups.
Reference
Naesilla N et al. Understanding the bidirectional relationship between chronic respiratory disease and cardiovascular disease using genetic evidence. Thorax. 2025;DOI: 10.1136/thorax-2024-222908.
