Idiopathic pulmonary fibrosis and the role of genetics in the era of precision medicine

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic, rare progressive lung disease, characterized by lung scarring and the irreversible loss of lung function. Two anti-fibrotic drugs, nintedanib and pirfenidone, have been demonstrated to slow down disease progression, although IPF mortality remains a challenge and the patients die after a few years from diagnosis. Rare pathogenic variants in genes that are involved in the surfactant metabolism and telomere maintenance, among others, have a high penetrance and tend to co-segregate with the disease in families. Common recurrent variants in the population with modest effect sizes have been also associated with the disease risk and progression. Genome-wide association studies (GWAS) support at least 23 genetic risk loci, linking the disease pathogenesis with unexpected molecular pathways including cellular adhesion and signaling, wound healing, barrier function, airway clearance, and innate immunity and host defense, besides the surfactant metabolism and telomere biology. As the cost of high-throughput genomic technologies continuously decreases and new technologies and approaches arise, their widespread use by clinicians and researchers is efficiently contributing to a better understanding of the pathogenesis of progressive pulmonary fibrosis. Here we provide an overview of the genetic factors known to be involved in IPF pathogenesis and discuss how they will continue to further advance in this field. We also discuss how genomic technologies could help to further improve IPF diagnosis and prognosis as well as for assessing genetic risk in unaffected relatives. The development and validation of evidence-based guidelines for genetic-based screening of IPF will allow redefining and classifying this disease relying on molecular characteristics and contribute to the implementation of precision medicine approaches.

Identification of Hub Genes in Idiopathic Pulmonary Fibrosis and Their Association with Lung Cancer by Bioinformatics Analysis

“…Our meta-analysis revealed that IL6 remained downregulated in IPF tissue samples compared to the control samples, although this decrease did not reach statistical significance according to the results obtained from validation of the GSE92592 dataset. The absence of statistical significance may be related to the sample size and the large biological variability between patients with IPF, which makes it difficult to detect significant differences in a smaller dataset [101,102]. Despite this discrepancy with the literature on IL-6 expression, we consider our findings valuable and enriching for the field of IPF research.…”

Idiopathic Pulmonary Fibrosis: Where do We Stand and How Far to Go?

“…Gene variations, including rs111521887 and rs5743894, detected in the TOLLIP introns have been associated with IPF susceptibility and have led to a 40-50% reduction in TOLLIP gene expression in the lung [186]. Interestingly, the rs5743890G allele, while associated with lower IPF susceptibility, is linked to higher mortality in IPF, indicating a potential genetic basis for different clinical outcomes [244]. This TLR inhibitory protein could be useful in identifying various IPF therapy responses in different genotypes [245].…”