Neutrophil-to-Lymphocyte Ratio, Lung Function, COPD, and <i>AHRR</i> Hypomethylation in Older Adults: A 30-Year Longitudinal Study of US Veterans

Abstract

Background: Chronic obstructive pulmonary disease (COPD) is a critical public health burden. The neutrophil-to-lymphocyte ratio (NLR) is an inflammation biomarker and predictor for COPD morbidity and mortality; however, its associations with lung function decline and COPD development are incompletely understood. Methods: We performed a longitudinal study of US veterans with >30 years of follow-up to investigate the associations of NLR with lung function, COPD, and the hypomethylation of cg05575921, the top DNA methylation marker of lung function changes in response to tobacco smoking. This study included 7466 visits from 1549 white males each examined up to 13 times during 1982-2018. NLR was estimated based on automated whole blood cell counts, and cg05575921 profile was measured in blood DNA using Illumina 450K BeadChip from a subset of 1228 visits. Findings: A one-unit increase in NLR was associated with a 0∙021-liter, 0∙016-liter, 0∙29%, and 3∙7-liters/min lower FEV1, FVC, FEV1/FVC, and MMEF, respectively (p-values <0∙001). NLR changes up to ~10 years were robustly associated with corresponding longitudinal changes in lung function. Further, this increase in NLR was associated with 9% higher odds of COPD (95% CI: 1∙03-1∙15) and 27% higher risk of incident COPD (95% CI: 1∙07-1∙51). NLR was associated with cg05575921 hypomethylation, which may mediate the adverse effect of NLR-related inflammation on lung function. Applying NLR and cg05575921 in combination could classify the extent of lung function impairment and COPD risk. Interpretation: NLR may be a valuable biomarker to promote the primary prevention of lung function decline and COPD in the general population. Funding Statement: This work was supported by the National Institute of Environmental Health Sciences (grants P30ES009089, R01ES021733, R01ES025225, and R01ES027747). The VA Normative Aging Study is supported by the Cooperative Studies Program/Epidemiology Research and Information Center of the U.S. Department of Veterans Affairs and is a component of the Massachusetts Veterans Epidemiology Research and Information Center, Boston, Massachusetts. Declaration of Interests: The authors have no conflicts of interest to declare. Ethics Approval Statement: The NAS was approved by the Department of Veterans Affairs Boston Healthcare System, and each subject provided written informed consent before participation.