Large-Scale Disease-Wide Association Study Identified Predisposition Links Between Influenza and Cardiovascular...

Influenza remains a major global health threat and, akin to "long COVID," has been linked to prolonged multi-organ comorbidities ("long flu"). Cardiovascular diseases (CVDs) are increasingly recognized in the pathogenesis of influenza, yet most prior work emphasizes acute or short-term outcomes and rarely contrasts multiple endpoints over extended horizons.

This study conducted a disease-wide association study (DWAS), assembling individuals with clinically coded influenza without pneumonia (n = 5136) and population comparators (n = 314,673). Using age- and sex-adjusted Cox models, this analysis screened 106 comorbid endpoints classified by ICD-10/ICD-O-3 and FinnGen disease taxonomy. Associations were evaluated bidirectionally-before influenza (predisposition) and after influenza (subsequent risk)-within prespecified 1-, 5-, and 15-year time windows.

Influenza showed broad associations spanning circulatory, nervous, endocrine-metabolic, respiratory, musculoskeletal, and other organ systems. CVD endpoints demonstrated the most persistent and directionally consistent DWAS signals. In pre-influenza analyses, greater baseline cardiovascular burden-including heart failure, coronary atherosclerosis, hypertension, major coronary heart disease, atrial fibrillation/flutter, myocardial infarction, stroke, pulmonary embolism, and venous thromboembolism-was associated with higher susceptibility to subsequent influenza. In post-influenza analyses, elevated risks remained for key CVD outcomes-atrial fibrillation/flutter, heart failure, myocardial infarction, and stroke. Non-cardiovascular endpoints (e.g., migraine, sleep apnoea, spinal stenosis, osteoporosis, chronic obstructive pulmonary disease, diabetic nephropathy, and chronic kidney disease) also showed bidirectional associations with influenza, thereby situating CVD within a broader comorbidity and frailty context of influenza.

In this population-scale DWAS, CVDs emerged as the most significant comorbidities of influenza. Conceptualizing influenza as a "cardiovascular stress test" supports targeted prevention (e.g., vaccination prioritization) and intensified cardiovascular risk management around influenza seasons. While the biological mechanism remains unclear, this study will motivate future studies integrating biomarkers, cardiovascular imaging, and virologic-immunologic profiling to disentangle causal mechanisms.