Dissecting the associations of cardiovascular health, biological aging, and blood DNA methylation signatures with chronic respiratory disease risk

Abstract

The interplay between cardiovascular health (CVH), biological aging, and underlying epigenetic mechanisms in relation to chronic respiratory diseases (CRDs) remains unclear. We conducted a large-scale prospective cohort study including 181,955 participants from the UK Biobank. Cardiovascular health (CVH) was assessed using the Life’s Essential 8 (LE8) score, and biological aging was evaluated using phenotypic age acceleration (PhenoAgeAccel). Cox proportional hazards models were used to examine the associations of LE8 score and PhenoAgeAccel with the risk of overall chronic respiratory diseases (CRDs) and CRD subtypes, including chronic obstructive pulmonary disease (COPD), asthma, and idiopathic pulmonary fibrosis (IPF). Joint effects and interactions between CVH and biological aging were further examined. Epigenetic Mendelian randomization (MR) and colocalization analyses were performed to prioritize aging- and LE8-related DNA methylation (DNAm) CpG sites associated with COPD, asthma, and IPF. Finally, a three-stage MR analysis integrating DNAm, gene expression, and CRD risk was conducted to explore potential regulatory pathways. Higher PhenoAgeAccel was associated with increased risks of overall CRDs and CRD subtypes, whereas a higher LE8 score was associated with lower disease risk. Joint analysis showed that participants with high CVH and biologically younger status had the lowest risks of overall CRDs and each subtype. Additive interaction analyses indicated that the coexistence of low CVH and biologically older status conferred excess risks of overall CRDs, COPD, and IPF. Epigenetic MR and colocalization analyses further prioritized 287 aging-related and 42 LE8-related DNAm CpG sites associated with COPD, asthma, and IPF. The three-stage MR analysis suggested that 14 CpG sites may influence CRD risk through changes in the expression of 8 mapped genes. These findings highlight the potential interplay between cardiovascular health, biological aging, and underlying epigenetic mechanisms in the development of CRDs and their subtypes.