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

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 theCCL18gene on CCL18 expression and survival in IPF. Serum CCL18 levels and four SNPs in theCCL18gene were analyzed in 77 Dutch IPF patients and 349 healthy controls (HCs).CCL18mRNA 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 byrs2015086C > T genotype, with the highest CCL18-levels with the presence of the C-allele. ConstitutiveCCL18mRNA-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 theCCL18-gene accounts for differences inCCL18mRNA-expression and serum-levels and influences survival in IPF.