Recent advances in the genetics of idiopathic pulmonary fibrosis

Abstract

Purpose of review Genetics contributes substantially to the susceptibility to idiopathic pulmonary fibrosis (IPF). Genetic studies in sporadic and familial disease have identified several IPF-associated variants, mainly in telomere-related and surfactant protein genes. Here, we review the most recent literature on genetics of IPF and discuss how it may contribute to disease pathogenesis. Recent findings Recent studies implicate genes involved in telomere maintenance, host defence, cell growth, mammalian target of rapamycin signalling, cell–cell adhesion, regulation of TGF-β signalling and spindle assembly as biological processes involved in the pathogenesis of IPF. Both common and rare genetic variants contribute to the overall risk of IPF; however, while common variants (i.e. polymorphisms) account for most of the heritability of sporadic disease, rare variants (i.e. mutations), mainly in telomere-related genes, are the main contributors to the heritability of familial disease. Genetic factors are likely to also influence disease behaviour and prognosis. Finally, recent data suggest that IPF shares genetic associations – and probably some pathogenetic mechanisms – with other fibrotic lung diseases. Summary Common and rare genetic variants are associated with susceptibility and prognosis of IPF. However, many of the reported variants fall in noncoding regions of the genome and their relevance to disease pathobiology remains to be elucidated.

Telomere length is an epigenetic trait – Implications for the use of telomerase-deficient organisms to model human disease

“…In addition to natural variation of telomere length and disease, mutations in the genes encoding telomerase subunits and its associated proteins, lead to syndromes called telomere biology disorders (TBDs) (Raj et al, 2023;Revy et al, 2023;Carvalho et al, 2022). These include rare diseases (Alter et al, 2012;Garofola et al, 2023), such as dyskeratosis congenita and Hoyeraal-Hreidarsson syndrome, but also chronic diseases, such as idiopathic pulmonary fibrosis (IPF) (Spagnolo and Lee, 2023). IPF affects ∼5 million people worldwide and half of them have telomeres with lengths in the lower 1% of the average distribution for their age group.…”

Somatic Mutations: The Next Frontier in Demystifying Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis?

“…The pathogenesis of many chronic lung diseases, such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), is driven by the complex interplay of genetic susceptibility, environmental exposures, and aging. Although there has been amazing progress in our understanding of the association of inherited gene mutations with COPD ( 1 ) and IPF ( 2 ), there has literally been no interest in somatic mutations, changes in cellular DNA that accumulate through the lifetime of the organism, which quite often reflect the impact of environmental exposures and are now increasingly studied in nonmalignant complex diseases ( 3 ).…”