Dymph Klay1, Joanne J van der Vis1,2, Suzan M Roothaan3, Tri Q Nguyen3, Jan C Grutters1,4, Roel Goldschmeding3, Coline H M van Moorsel5,6. 1. Interstitial Lung Diseases Center of Excellence, Department of Pulmonology, St. Antonius Hospital, Nieuwegein, The Netherlands. 2. Department of Clinical Chemistry, St. Antonius Hospital, Nieuwegein, The Netherlands. 3. Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. 4. Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands. 5. Interstitial Lung Diseases Center of Excellence, Department of Pulmonology, St. Antonius Hospital, Nieuwegein, The Netherlands. c.van.moorsel@antoniusziekenhuis.nl. 6. Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands. c.van.moorsel@antoniusziekenhuis.nl.
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.
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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