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.

Lung regeneration: diverse cell types and the therapeutic potential

“…177 In mouse models, abnormal expression of genes specifically expressed in the respiratory system, such as surfactant protein C (SFTPC) deficiency and mucin 5B (MUC5B) overexpression, can also cause spontaneous lung diseases similar to clinical phenotypes. [178][179][180][181]…”

“…Adenosine deaminase‐deficient mice show chronic lung disease features, such as progressive airway inflammation and airway remodeling, with elevated adenosine 177 . In mouse models, abnormal expression of genes specifically expressed in the respiratory system, such as surfactant protein C (SFTPC) deficiency and mucin 5B (MUC5B) overexpression, can also cause spontaneous lung diseases similar to clinical phenotypes 178–181 …”

Integrated multiomic analysis identifiesTRIP13as a mediator of alveolar epithelial type II cell dysfunction in idiopathic pulmonary fibrosis

“…Current therapies only delay progression (2) , leaving lung transplant as the sole remaining option (3,4) . Risk factors include older age, male sex, smoking history (1) , other inhalant exposures (5) and in familial cases, inherited mutations (6,7) primarily in genes linked to alveolar epithelial type II (AT2) cell biology (8)(9)(10)(11)(12) , implicating AT2 cells in IPF pathogenesis (13) . Furthermore, mutations affecting telomere maintenance have been implicated in both familial and sporadic IPF (14) .…”

“…Environmental factors such as tobacco smoke and pollutants, and intrinsic factors such as aging, all implicated in IPF pathogenesis, can alter the epigenome (23, 24) . The contribution of epigenetic alterations to IPF has been studied in the limited context of genes of high interest, particularly the role of DNA methylation at certain target genes (7, 25, 26) , and global imbalances in histone deacetylase activity (27) . To our knowledge, no detailed investigation of epigenomic dysregulation within resident alveolar epithelial populations in IPF has been performed.…”

Exploring the Potential Role of Metabolomics in COPD: A Concise Review

“…Metabolomics thus seems to be a useful scientific tool to enhance our understanding of disease mechanisms and to complement what genetics can already explain about lung diseases. In the future, it may not only aid in obstructive diseases but also in restrictive diseases, such as Interstitial Lung Diseases (ILD) [ 5 , 6 ].…”