Circulating Biomarkers in Young Individuals With Low Peak FEV(1)

Abstract

It is now well established that there is a range of lunch function trajectories throughout the life course (1,2). Specifically, 4-12% of young adults in the general population never achieve normal peak lung function, as determined by FEV (1), measurement (3). These individuals are at higher risk of developing chronic obstructive pulmonary disease (COPD) in adulthood (4), suffer a higher prevalence and a decade earlier incidence of cardiovascular metabolic disorders, and die prematurely (3,5). The biological mechanisms underlying these observations are unknown. Older patients with COPD often present abnormal levels of circulatory inflammatory markers (IL-6, IL-8, CCL19), (6), pneumo-proteins (CC16, SP-D, sRAGE, CCL18) (6) and ageing hallmarks (telomere attrition and mitochondrial damage) (7). Whether or not these biological abnormalities also occur in young individuals with low peak lung function has not been investigated before. To explore this, we studied 300 individuals aged 25-35 years from the Lifelines Cohort Study (8) with FEV1 < (n=147) or ≥ (n=153) than their lower limit of normal (LLN) for their age (according to the GLI equations). Demographic and clinical factors had been recorded as described elsewhere (8). Because groups were balanced by sex and smoking exposure, their potential effect could not be investigated here. The serum levels of IL-8, IL-6, sRAGE, SP-D, CCL2, CCL19, Pentraxin-3, TSLP, CC16, CCL18, BNDF, Leptin, vWFA-2, Collagen I 1, all previously associated with COPD (6), were quantified using the Luminex MAGPIX® platform (R&D systems). Because IL-6 and TSLP concentration were below the detection level of the assay in more than 80% of samples, they were excluded from analysis. For the included biomarkers, determinations below the detection limit were imputed with a 1/4 of that value. The maximum number of imputed samples was n=11 (out of 300 measured, i.e. 3.7%) for both IL-8 and Pentraxin-3. Telomere length and the ratio between mitochondrial to nuclear DNA (12SrRNA/RNAseP)), two well-stablished aging hallmarks (7), were measured by quantitative PCR(qPCR) in whole blood DNA. Differences between groups were compared using the Mann57 Whitney U test. A step-wise multivariate logistic regression model that included clinical factors associated with low peak FEV1 (table 1) (3, 9-11)) and the biomarkers measured here was used to identify variables independently associated to FEV1 <LLN.