Abstract
BACKGROUND: Leukocyte composition ratios derived from blood genome-wide methylation (DNAm-derived LCRs), reflecting systemic inflammation, remain unclear in relation to various mortality outcomes. METHODS: We performed an epigenome-wide analysis to identify the association of DNAm-derived LCRs with all-cause mortality, cancer-specific mortality, and lung-cancer-specific mortality in a large prospective cohort study with 17 years follow-up. RESULTS: Strong associations of multiple LCRs are seen for all mortality outcomes. The neutrophil-to-B-cell ratio was strongly associated with all-cause mortality (HR per SD increase, 1.20; 95% CI, 1.10-1.31), the neutrophil-to-lymphocyte ratio with cancer-specific mortality (HR, 1.28; 1.11-1.49), and the lymphocyte-to-monocyte ratio with lung-cancer-specific mortality (HR, 0.53; 0.38-0.75). The consistency of HR estimations across 11-year, 14-year, and 17-year follow-ups reinforces these findings. Several LCRs show stronger associations in females and younger participants. CONCLUSIONS: Our study identifies DNAm-derived LCRs as particularly useful measures for quantifying cancer mortality risk over long-term follow-ups exceeding a decade.