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Transforming Growth Factor-ß Gene Polymorphisms in Sarcoidosis Patients With and Without Fibrosis^*

^* From the Heart Lung Centre Utrecht, St. Antonius Hospital, Departments of Pulmonology (Mr. Kruit, and Drs. Grutters and van den Bosch), and Clinical Chemistry (Drs. Ruven and van Moorsel), Nieuwegein, the Netherlands; and Institute of Clinical Chemistry and Pathobiochemistry (Dr. Weiskirchen and Ms. Mengsteab), RWTH-University Hospital, Aachen, Germany.

Correspondence to: Jules M. M. van den Bosch, MD, PhD, Department of Pulmonology, St. Antonius Hospital, Koekoekslaan 1, 3435 CM, Nieuwegein, the Netherlands; e-mail: j.vandenbosch{at}antonius.net

Abstract

Study objectives: Pulmonary fibrosis develops in approximately 25% of patients with chronic sarcoidosis. Transforming growth factor (TGF)-ß1 plays a central role in fibrosis, and accruing reports address the implication of TGF-ß2 and TGF-ß3 in this process. We determined whether single-nucleotide polymorphisms (SNPs) in the TGF-ß1, TGF-ß2, and TGF-ß3 genes might contribute to pulmonary fibrosis in sarcoidosis patients.

Setting: A hospital in the Netherlands.

Design: Five SNPs per TGF-ß gene were investigated.

Patients and control subjects: Patients with either acute/self-remitting sarcoidosis (n = 50) and Löfgren 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-ß3 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-ß3 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-ß3 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-ß2 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-ß1 gene polymorphisms were not associated with fibrosis.

Conclusions: This study is the first to suggest the implication of genetic variation of TGF-ß3 in the predilection for pulmonary fibrosis developing in sarcoidosis patients.

Key Words: genetic predisposition • pulmonary fibrosis • single-nucleotide polymorphism • transforming growth factor-ß