Genetic Variation in CCL18 Gene Influences CCL18 Expression and Correlates with Survival in Idiopathic Pulmonary Fibrosis—Part B

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with high mortality. CC-chemokine ligand 18 (CCL18) is predictive of survival in IPF. We described correlation of CCL18 serum levels with the genotype of rs2015086 C > T polymorphism the CCL18-gene, which was associated with survival in a pre-antifibrotic cohort (Part-A). Herein (Part-B), we aimed to validate these findings and to study the effects of antifibrotics. Two cohorts were prospectively recruited, cohort-A (n = 61, pre-antifibrotic) and cohort B (n = 101, received antifibrotics). Baseline CCL18 serum level measurement by enzyme-linked immunosorbent assay (ELISA, serially in cohort B) and genotyping of rs2015086 was performed and correlated with clinical outcomes. The CT genotype was present in 15% and 31% of patients. These patients had higher CCL18 levels compared to the TT-genotype (cohort-A: 234 vs. 115.8 ng/mL, p < 0.001; cohort B: 159.5 vs. 120 ng/mL, p = 0.0001). During antifibrotic therapy, CCL18 increased (p = 0.0036) regardless of rs2015086-genotype and antifibrotic-agent. In cohort-A, baseline CCL18-cutoff (>120 ng/mL) and CT-genotype were associated with mortality (p = 0.041 and p = 0.0051). In cohort-B, the CCL18-cutoff (>140 ng/mL) was associated with mortality (p = 0.003) and progression (p = 0.004), but not the CT/CC-genotype. In conclusion, we validated the correlation between rs2015086-genotype and CCL18 serum levels, which was predictive of (progression-free)-survival in two prospective validation cohorts.

Predictive biomarkers of disease progression in idiopathic pulmonary fibrosis

“…In the anti-fibrosis treatment cohort, increased CCL18 was associated with poor prognosis. The genotype of the CCL18 gene promoter SNP has no predictive value; furthermore, CCL18 level increased no matter the effect of anti-fibrosis (nintedanib and pirfenidone) treatment [ 42 , 15 ]. Another study showed that CCL18 cannot predict the progression of IPF [ 11 ].…”

“… Majewski S, 2022 [ 14 ] YKL-40 Single-center, case-control study IPF: n = 25 Control subject: n = 20 24 Serum YKL-40 concentration may be related to the response to anti-fibrosis therapy of IPF patients. Caliskan C, 2020 [ 15 ] CCL18 Multicenter, prospective, cohort study Cohort A: n = 61 Cohort B: n = 126 Cohort A: 48 Cohort B: 36 Serum CCL18 level is associated with the CCL18 rs2015086 genotype and predicts mortality and disease progression of IPF patients. Akiyama N, 2020 [ 16 ] S100A4 Single-center, case-control study IPF: n = 95 Control subject: n = 50 24 High serum S100A4 level is independently associated with high disease progression and mortality.…”

Towards Treatable Traits for Pulmonary Fibrosis

“…Previous work has shown that alveolar macrophages from patients with several types of fibrotic lung disease show increased expression of the pro-Th2-inflammatory cytokine CCL 18, which seems to represent a feed-forward mechanism in the fibrotic process [ 53 ]. CCL18 expression has been associated with survival in patients with IPF and patients with CTD-ILD due to systemic sclerosis [ 54 , 55 , 56 ]. Gene expression studies performed on peripheral blood also support the role of inflammatory processes in progression of IPF [ 57 , 58 , 59 , 60 ], and in IPF lungs there is increased expression of genes related to inflammatory processes in fibrotic and non-fibrotic areas [ 61 ].…”