Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease, characterized by fibroblast proliferation and extracellular matrix deposition. CC-chemokine ligand 18 (CCL18) upregulates the production of collagen by lung fibroblasts and is associated with mortality. This study was designed to evaluate the influence of single nucleotide polymorphisms (SNPs) in the CCL18 gene on CCL18 expression and survival in IPF. Serum CCL18 levels and four SNPs in the CCL18 gene were analyzed in 77 Dutch IPF patients and 349 healthy controls (HCs). CCL18 mRNA expression was analyzed in peripheral blood mononuclear cells (PBMCs) from 18 healthy subjects. Survival analysis was conducted, dependent on CCL18-levels and -genotypes and validated in two German IPF cohorts (Part B). IPF patients demonstrated significantly higher serum CCL18 levels than the healthy controls (p < 0.001). Both in IPF patients and HCs, serum CCL18 levels were influenced by rs2015086 C > T genotype, with the highest CCL18-levels with the presence of the C-allele. Constitutive CCL18 mRNA-expression in PBMCs was significantly increased with the C-allele and correlated with serum CCL18-levels. In IPF, high serum levels correlated with decreased survival (p = 0.02). Survival was worse with the CT-genotype compared to the TT genotype (p = 0.01). Concluding, genetic variability in the CCL18-gene accounts for differences in CCL18 mRNA-expression and serum-levels and influences survival in IPF.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease of the lung parenchyma, characterized by fibroblast proliferation and extracellular matrix deposition [1]
The characteristics of patients with available serum did not differ from the total group, as shown in SupPpollyemmoerpnhtiasmry TabAlelleSle1.anTdhGeesneortuypme levIePlFsfurthHeeraltmhyeaCsounrtreodls i(nn =a3s4e9)le*ction of 204 healthy controlsrs(781620m44ale (42%), 118 feAmale (58%), me9d7i(a63n%a)ge 40.1 years 4[8IQ0 (R692%9).5 – 51.0]) who were enriched for the presence of the minorGallele rs201505876(.3T7%he) characteristi2c1s8o(3f1t%h)ese healthy controls did not differ from the total group oAAfAGcontrols (p ra33n13g((44i03n%%g)) 0.768–0.999).11A3762n((34a99l%%ys))is of the derivation cohort showed that serum CC-chemokine ligand 18 (CCL18) leveGlsGwere significa13n(t1ly7%h)igher in the IP4F1p(1a2t%ie)nts
We found an association between the rs2015086 polymorphism and serum CCL18 levels in both the controls and patients
Summary
Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease of the lung parenchyma, characterized by fibroblast proliferation and extracellular matrix deposition [1]. A clear relationship has been demonstrated between the elevated serum levels of CCL18 and clinical outcomes in IPF patients, including survival [16] and acute exacerbation rate [20], and has been confirmed in data from two randomized controlled trials [13]. It was demonstrated that alveolar macrophages from patients with pulmonary fibrosis show an alternatively activated phenotype, which up-regulates the production of collagen by lung fibroblasts through the production of CCL18 [14]. We hypothesized that genetic variation in the CCL18 gene might be associated with increased CCL18 expression and may predispose to an unfavorable prognosis in subjects with IPF
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