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

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

MUC5B rs35705950 minor allele associates with older age and better survival in idiopathic pulmonary fibrosis

Background and Objective: The minor T-allele of the MUC5B promoter polymorphism rs35705950 is strongly associated with idiopathic pulmonary fibrosis (IPF). However, conflicting results have been reported on the relationship between the MUC5B minor allele and survival and it is unknown whether a specific subgroup of IPF patients might benefit from MUC5B minor allele carriage. We investigated the association between MUC5B rs35705950, survival and patient characteristics in a real-world population of European IPF patients. Methods: In this retrospective study, 1751 patients with IPF from 8 European centres were included. MUC5B rs35705950 genotype, demographics, clinical characteristics at diagnosis and survival data were analysed. Results: In a multi-variate Cox proportional hazard model the MUC5B minor allele was a significant independent predictor of survival when adjusted for age, sex, high resolution computed tomography pattern, smoking behaviour and pulmonary function tests in IPF. MUC5B minor allele carriers were significantly older at diagnosis (p = 0.001). The percentage of MUC5B minor allele carriers increased significantly with age from 44% in patients aged 75. In IPF patients aged <56, the MUC5B minor allele was not associated with survival. In IPF patients aged ≥56, survival was significantly better for MUC5B minor allele carriers (45 months [CI: 42–49]) compared to non-carriers (29 months [CI: 26–33]; p = 4 × 10 −12). Conclusion: MUC5B minor allele carriage associates with a better median transplant-free survival of 16 months in the European IPF population aged over 56 years. MUC5B genotype status might aid disease prognostication in clinical management of IPF patients