Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Jun 21;9(6):1940.
doi: 10.3390/jcm9061940.

Genetic Variation in CCL18 Gene Influences CCL18 Expression and Correlates with Survival in Idiopathic Pulmonary Fibrosis: Part A

Ivo A Wiertz  1 , Sofia A Moll  1 , Benjamin Seeliger  2 , Nicole P Barlo  1 , Joanne J van der Vis  3 , Nicoline M Korthagen  1 , Ger T Rijkers  3 , Henk J T Ruven  4 , Jan C Grutters  1   5 , Antje Prasse  2   6 , Coline H M van Moorsel  1
Affiliations

Genetic Variation in CCL18 Gene Influences CCL18 Expression and Correlates with Survival in Idiopathic Pulmonary Fibrosis: Part A

Ivo A Wiertz et al. J Clin Med. .

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.

Keywords: CCL18; chemokine; idiopathic pulmonary fibrosis; single nucleotide polymorphism; survival.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Linkage Disequilibrium (LD) map of four SNPs in the CCL18 gene: rs712040 (location: CCL18 promotor), rs2015086 (location: CCL18 promotor), rs712042 (location: CCL18 intron), rs712044 (location: CCL18 intron). The dark squares represent high r2 values and the triangle represents a haplotype block.
Figure 2
Figure 2
Serum CCL18 levels in healthy controls and patients with idiopathic pulmonary fibrosis (IPF) in the derivation cohort (A), depending on rs2015086 genotype in healthy controls (B), and IPF patients (C).
Figure 3
Figure 3
(A) mRNA expression of CCL18 in PBMCs from 18 healthy controls, expressed as the number of CCL18 transcripts per copy of β-actin, according to rs2015086 genotype. (B) Scatterplot showing the correlation between serum CCL18 levels and the number of CCL18 mRNA transcripts per copy of β-actin. Values on the X and Y-axis represent log-transformed values.
Figure 4
Figure 4
Kaplan–Meier curves for survival in patients with idiopathic pulmonary fibrosis, depending on a serum CCL18 level cut-off of 500 ng/mL (A); rs2015086-genotype (B), and a combination of CCL18 cut-off and rs2015086-genotype (C). P-values were calculated via the Log Rank Test using Kaplan–Meier curves.
See this image and copyright information in PMC

References

    1. Lederer D.J., Martinez F.J. Idiopathic Pulmonary Fibrosis. N. Engl. J. Med. 2018;378:1811–1823. doi: 10.1056/NEJMra1705751. - DOI - PubMed
    1. King T.E., Bradford W.Z., Castro-Bernardini S., Fagan E.A., Glaspole I., Glassberg M.K., Gorina E., Hopkins P.M., Kardatzke D., Lancaster L., et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N. Engl. J. Med. 2014;370:2083–2092. doi: 10.1056/NEJMoa1402582. - DOI - PubMed
    1. Richeldi L., Du Bois R.M., Raghu G., Azuma A., Brown K.K., Costabel U., Cottin V., Flaherty K.R., Hansell D.M., Inoue Y., et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N. Engl. J. Med. 2014;370:2071–2082. doi: 10.1056/NEJMoa1402584. - DOI - PubMed
    1. Somogyi V., Chaudhuri N., Torrisi S.E., Kahn N., Müller V., Kreuter M. The therapy of idiopathic pulmonary fibrosis: What is next? Eur. Respir. Rev. 2019;28:190021. doi: 10.1183/16000617.0021-2019. - DOI - PMC - PubMed
    1. Ley B., Collard H.R., King T.E. Clinical course and prediction of survival in idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 2011;183:431–440. doi: 10.1164/rccm.201006-0894CI. - DOI - PubMed

LinkOut - more resources