Dataset Information

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

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.

SUBMITTER: Wiertz IA

PROVIDER: S-EPMC7356165 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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

Wiertz Ivo A IA Moll Sofia A SA Seeliger Benjamin B Barlo Nicole P NP van der Vis Joanne J JJ Korthagen Nicoline M NM Rijkers Ger T GT Ruven Henk J T HJT Grutters Jan C JC Prasse Antje A van Moorsel Coline H M CHM

Journal of clinical medicine 20200621 6

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 <i>CCL18</i> gene on CCL18 expression and survival in IPF. Serum CCL18 levels and four SNPs in the <i>CCL18</i> gene were analy ...[more]

PMID: 32575869

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Project description:BackgroundCurrent research underscores the need to better understand the pathogenic mechanisms and treatment strategies for idiopathic pulmonary fibrosis (IPF). This study aimed to identify key targets involved in the progression of IPF.MethodsWe employed Mendelian randomization (MR) with three genome-wide association studies and four quantitative trait loci datasets to identify key driver genes for IPF. Prioritized targets were evaluated for respiratory insufficiency and transplant-free survival. The therapeutic efficacy of the core gene was validated in cellular and animal models. Additionally, we conducted a comprehensive evaluation of therapeutic value, pathogenic mechanisms, and safety through phenome-wide association study (PheWAS), mediation analysis, transcriptomic analyses, shared causal variant exploration, DNA methylation MR, and protein interactions.ResultsMultiple MR results revealed that BRSK2 has a significant pathogenic impact on IPF at both transcriptional and translational levels, with a lung tissue-specific association (OR = 1.596; CI, 1.300-1.961; Pval = 8.290 × 10 - 6). BRSK2 was associated with IPF progression driven by high-risk factors, with mediation effects ranging from 34.452 to 69.665%. Elevated BRSK2 expression in peripheral blood mononuclear cells correlated with reduced pulmonary function, while increased circulating BRSK2 levels suggested respiratory failure and shorter transplant-free survival in IPF patients. BRSK2 silencing attenuated lung fibrosis progression in cellular and animal models. Transcriptomic integration identified PSMB1, CTSD, and CTSH as significant downstream effectors of BRSK2, with PSMB1 showing robust shared causal variant support (PPH4 = 0.800). Colocalization analysis and phenotype scan deepened the pathogenic association of BRSK2 with IPF, while methylation MR analysis highlighted the critical role of epigenetic regulation in BRSK2-driven IPF pathogenesis. PheWAS revealed no significant drug-related toxicities for BRSK2, and its therapeutic potential was further underscored by protein interaction analyses.ConclusionsBRSK2 is identified as a critical pathogenic factor in IPF, with strong potential as a therapeutic target. Future studies should focus on its translational implications and the development of targeted therapies to improve patient outcomes.

Dataset Information

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

Publications

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

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