The Genetic and Epigenetic Footprint in Idiopathic Pulmonary Fibrosis and Familial Pulmonary Fibrosis: A State-of-the-Art Review

Abstract

Idiopathic pulmonary fibrosis (IPF) is a rare disease of the lung with a largely unknown etiology and a poor prognosis. Intriguingly, forms of familial pulmonary fibrosis (FPF) have long been known and linked to specific genetic mutations. There is little evidence of the possible role of genetics in the etiology of sporadic IPF. We carried out a non-systematic, narrative literature review aimed at describing the main known genetic and epigenetic mechanisms that are involved in the pathogenesis and prognosis of IPF and FPF. In this review, we highlighted the mutations in classical genes associated with FPF, including those encoding for telomerases (TERT, TERC, PARN, RTEL1), which are also found in about 10-20% of cases of sporadic IPF. In addition to the Mendelian forms, mutations in the genes encoding for the surfactant proteins (SFTPC, SFTPA1, SFTPA2, ABCA3) and polymorphisms of genes for the mucin MUC5B and the Toll-interacting protein TOLLIP are other pathways favoring the fibrogenesis that have been thoroughly explored. Moreover, great attention has been paid to the main epigenetic alterations (DNA methylation, histone modification and non-coding RNA gene silencing) that are emerging to play a role in fibrogenesis. Finally, a gaze on the shared mechanisms between cancer and fibrogenesis, and future perspectives on the genetics of pulmonary fibrosis have been analyzed.

Keywords: ABCA3; MUC5B; epigenetic; familial pulmonary fibrosis; genetic; idiopathic pulmonary fibrosis; surfactant; telomerase; telomere; therapy.

Figure 1

Main risk factors for the development of pulmonary fibrosis.

Figure 2

Main profibrotic mechanisms secondary to mutations or polymorphisms in the genes for telomerases, surfactant proteins, mucin 5B. Mutations in TERT, TERC, PARN and RTEL1 decrease the activity of telomerase, thus resulting in augmented shortening of telomeres. SFTPC, SFTPA1, SFTPA2, ABCA3 normally modulate and stabilize the alveolar surfactant tension; when altered, they can induce an increased stress of the endoplasmic reticulum, which finally lead to epithelial-mesenchymal transitions and apoptosis of type 2 alveolar cells. Polymorphisms of MUC5B, a regulatory mucin, are responsible of mucociliary disfunction, with impaired clearance and enhanced mucus production, which predisposes to bacterial overgrowth and infections.