Transforming growth factor-β gene polymorphisms in sarcoidosis patients with and without fibrosis

Study objectives: Pulmonary fibrosis develops in approximately 25% of patients with chronic sarcoidosis. Transforming growth factor (TGF)-beta 1 plays a central role in fibrosis, and accruing reports address the implication of TGF-beta 2 and TGF-beta 3 in this process. We determined whether single-nucleotide polymorphisms (SNPs) in the TGF-beta 1, TGF-beta 2, and TGF-beta 3 genes might contribute to pulmonary fibrosis in sarcoidosis patients. Setting: A hospital in the Netherlands. Design: Five SNPs per TGF-beta gene were investigated. Patients and control subjects: Patients with either acute/self-remitting sarcoidosis (n = 50) and Lofgren syndrome (n = 46) or chronic disease with fibrosis (n = 24) and without fibrosis (n = 34) were assessed over a 4-year follow-up period. The control subjects included 315 individuals. Measurements and results: Polymorphism frequencies were not discordant between the patients and control subjects. The TGF-beta 3 4875 A allele was significantly higher in fibrotic patients (carrier frequency, 0.29) than in patients with acute/self-remitting (0.06) and chronic (0.03) sarcoidosis combined (corrected p = 0.01; odds ratio [OR], 7.9). The TGF-beta 3 17369 C allele carrier frequency was significantly higher in fibrotic patients (0.29) compared to acute/self-remitting (0.08) and chronic (0.06) patients combined (corrected p = 0.05; OR, 5.1). Although not significant after correction, the TGF-beta 3 15101 G allele carrier frequency was lower in fibrotic patients (0.79) compared to acute/self-remitting (0.94) and chronic (1.00) patients combined (p = 0.02; corrected p = 0.1; OR, 0.15). The TGF-beta 2 59941 G allele was more abundant in fibrotic patients (carrier frequency, 0.62) compared to patients with acute/self-remitting (0.41) and chronic sarcoidosis combined (0.28) [p = 0.04; corrected p = 0.2; OR, 2.9]. TGF-beta 1 gene polymorphisms were not associated with fibrosis. Conclusions: This study is the first to suggest the implication of genetic variation of TGF-beta 3 in the predilection for pulmonary fibrosis developing in sarcoidosis patients.