The genetic basis of idiopathic pulmonary fibrosis

Abstract

Throughout the past decade, there have been substantial advances in understanding the pathogenesis of idiopathic pulmonary fibrosis (IPF). Recently, several large genome-wide association and linkage studies have identified common genetic variants in more than a dozen loci that appear to contribute to IPF risk. In addition, family-based studies have led to the identification of rare genetic variants in genes related to surfactant function and telomere biology, and mechanistic studies suggest pathophysiological derangements associated with these rare genetic variants are also found in sporadic cases of IPF. Current evidence suggests that rather than existing as distinct syndromes, sporadic and familial cases of IPF (familial interstitial pneumonia) probably reflect a continuum of genetic risk. Rapidly evolving bioinformatic and molecular biology techniques, combined with next-generation sequencing technologies, hold great promise for developing a comprehensive, integrated approach to defining the fundamental molecular mechanisms that underlie IPF pathogenesis.

Figure 1

Proposed model of gene × environment interactions in the pathogenesis of pulmonary fibrosis.

Figure 2. Paradigm to develop an integrated model of genetic risk for IPF

Future studies identifying and characterizing the role of genetic variants in IPF will require integration of next-generation sequencing technologies, bioinformatics, and use of state-of-the-art molecular biology in cell and animal models. Identification of variants by whole exome sequencing (WES) or whole-genome-sequencing (WGS) will require strategic bioinformatics approaches. These genetic variants will require functional validation in cell and animal models; characterizing the effects of these genetic variants on gene expression profiles will require integration of sequencing and bioinformatics technologies.