High serum YKL-40 level in a cohort of octogenarians is associated with increased risk of all-cause mortality

Abstract

YKL-40 is secreted by macrophages, neutrophils, chondrocytes, endothelial-, vascular smooth muscle- and cancer cells. Interleukin (IL)-6 stimulates YKL-40 production in human in vivo studies. High serum YKL-40 is associated with poor prognosis in patients with inflammatory diseases and cancer. We studied whether serum YKL-40 was associated with systemic low-level inflammation, an immune risk phenotype, and mortality in relatively healthy 80-year old humans. Serum YKL-40, IL-6 and tumour necrosis factor (TNF)-alpha were measured by enzyme-linked immunosorbent assays (ELISAs) in octogenarians (n = 151) and serum YKL-40 in 18-30-year-olds (n = 89). Fifty-one of the octogenarians died during the 6-year follow-up. Serum YKL-40 in octogenarians was higher compared to the level in young people (median 116 versus 31 microg/l, P < 0.0005). Serum YKL-40 correlated with serum IL-6 in elderly women (Spearman's rho = 0.30, P = 0.009) and men (rho = 0.25, P = 0.003), but only with serum TNF-alpha (rho = 0.23, P = 0.05) and C-reactive protein (CRP) (rho = 0.57, P < 0.0005) among the elderly women. In addition, high serum level of YKL-40 was associated with a low CD4 : CD8 cell ratio. Univariate analysis of serum YKL-40 (logarithmically transformed and divided by tertiles) showed significant association with all-cause mortality [tertile 3: hazard ratio (HR) = 2.38, 95% confidence interval (CI): 1.19-4.78, P = 0.02]. The effect persisted after adjusting for potential confounders (sex, smoking, body mass index, chronic disease and anti-inflammatory medicine). These results suggest that serum YKL-40 is a prognostic and sensitive biomarker of all-cause mortality in octogenarians.