Abstract
Purpose
Connective tissue growth factor (CTGF) is an important mediator in fibrotic disease. Single nucleotide polymorphisms (SNPs) in CTGF have been found to be associated with different fibrotic diseases and CTGF protein was found to be upregulated in lung tissue, bronchoalveolar lavage cells, and plasma of idiopathic pulmonary fibrosis (IPF) patients. We investigated whether genetic variants predispose to sporadic IPF (spIPF), familial pulmonary fibrosis (FPF), and connective tissue disease associated ILD (CTD-ILD).
Methods
In total, 294 patients with spIPF and 294 healthy individuals were genotyped for CTGF rs12526196, rs9402373, rs6918698, and rs9399005. For replication of CTGF rs6918698 findings in pulmonary fibrosis, 128 patients with FPF, 125 with CTD-ILD, and an independent control cohort of 130 individuals were included. Lung tissue of 6 IPF patients was stained for CTGF to assess pulmonary localization.
Results
Of the four SNPs, only the minor allele frequency (MAF) of CTGF rs6918698 deviated between spIPF (MAF 0.41) and controls (MAF 0.47; OR 0.774 (0.615–0.975); p = 0.030). Further comparison of CTGF rs6918698G showed a difference between FPF (MAF 0.33) and controls (MAF 0.48; OR 0.545 (0.382–0.778); p = 0.001), but not with CTD-ILD. CTGF was localized in alveolar and bronchiolar epithelium, alveolar macrophages, myofibroblasts and endothelium and highly expressed in the basal cell layer of sandwich foci.
Conclusion
CTGF rs6918698G associates with spIPF and with FPF, but not with CTD-ILD in a Dutch cohort. CTGF is localized in lung tissue involved in IPF pathogenesis. Further research into the role of this SNP on CTGF expression and fibrogenesis is warranted.
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Data availability
The data that support the findings of this study are available from the corresponding author, CvM, upon reasonable request.
Code availability
Not applicable
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Funding
This research was funded by ZonMW-TopZorg St Antonius Science Corner grant (Topzorg Grant, Number 842002001) and Prof. Dr. Jaap Swierenga foundation.
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DK and CHMM devised the project. DK wrote the manuscript and performed the analyses. SMR and JJV performed the experiments. TQN helped with the selection and annotation of figures. CHMM supervised the project. All authors commented on previous versions of the manuscript and approved the final manuscript.
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This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by Medical research Ethics Committees United (MEC-U) of the St Antonius hospital (R05-08A).
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Klay, D., van der Vis, J.J., Roothaan, S.M. et al. Connective Tissue Growth Factor Single Nucleotide Polymorphisms in (Familial) Pulmonary Fibrosis and Connective Tissue Disease Associated Interstitial Lung Disease. Lung 199, 659–666 (2021). https://doi.org/10.1007/s00408-021-00494-y
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DOI: https://doi.org/10.1007/s00408-021-00494-y