Genetics and Genomics of Pulmonary Fibrosis: Charting the Molecular Landscape and Shaping Precision Medicine

Abstract

Recent genetic and genomic advancements have elucidated the complex etiology of idiopathic pulmonary fibrosis (IPF) and other progressive fibrotic interstitial lung diseases (ILDs), emphasizing the contribution of heritable factors. This state-of-the-art review synthesizes evidence on significant genetic contributors to pulmonary fibrosis (PF), including rare genetic variants and common SNPs. The MUC5B promoter variant is unusual, a common SNP that markedly elevates the risk of early and established PF. We address the utility of genetic variation in enhancing understanding of disease pathogenesis and clinical phenotypes, improving disease definitions, and informing prognosis and treatment response. Critical research gaps are highlighted, particularly the underrepresentation of non-European ancestries in PF genetic studies and the exploration of PF phenotypes beyond usual interstitial pneumonia/IPF. We discuss the role of telomere length, often critically short in PF, and its link to progression and mortality, underscoring the genetic complexity involving telomere biology genes (TERT, TERC) and others like SFTPC and MUC5B. In addition, we address the potential of gene-by-environment interactions to modulate disease manifestation, advocating for precision medicine in PF. Insights from gene expression profiling studies and multiomic analyses highlight the promise for understanding disease pathogenesis and offer new approaches to clinical care, therapeutic drug development, and biomarker discovery. Finally, we discuss the ethical, legal, and social implications of genomic research and therapies in PF, stressing the need for sound practices and informed clinical genetic discussions. Looking forward, we advocate for comprehensive genetic testing panels and polygenic risk scores to improve the management of PF and related ILDs across diverse populations.

Keywords: MUC5B promoter variant; genetic variants; interstitial lung diseases; precision medicine; pulmonary fibrosis.

Figure 1.

The multidimensional etiology of pulmonary fibrosis (PF). This figure illustrates the confluence of genetic predisposition, epigenetic regulation, and environmental factors integral to developing PF. The model emphasizes the role of genetic susceptibilities, such as PF-associated polymorphisms and epigenetic modifications, in altering gene expression due to environmental stimuli, reinforcing the importance of genetic and genomic research in developing personalized PF treatments.

Figure 2.

Chronological overview of major genomic technological advances with a focus on the genetics of pulmonary fibrosis (dark blue). The timeline indicates pivotal milestones, such as the establishment of Sanger sequencing and the Human Genome Project, leading up to recent developments in spatial genomics and human cell atlas projects (, –, –50, 59, 69, 74, 153, 196, 268, 326, 327). The lower portion of the figure depicts the increase in the amount of genomic data generated per run and spans the time-course of progression from basic techniques like restriction fragment length polymorphism (RFLP) to more data-intensive methods like whole-genome sequencing (WGS). Cas9 = CRISPR-associated protein 9; CRISPR = clustered regularly interspaced short palindromic repeats; FDA = U.S. Food and Drug Administration; GWAS = genome-wide association studies; ILA = interstitial lung abnormalities; IPF = idiopathic pulmonary fibrosis; NGS = next-generation sequencing.

Figure 3.

Conceptual model of the integrated pathophysiological mechanisms, genetic contributors, and cellular dynamics in pulmonary fibrosis (PF). This figure illustrates the complex and intersecting roles of risk genes across the evolution of PF, which likely occurs asynchronously in the lung. Initial responses to epithelial stress, which may involve a broad spectrum of susceptibility genes including SFTPC, SFTPA2, DSP, FAM13A, and MUC5B, lead to autonomous epithelial cell dysfunction and/or indirectly lead to compromised barrier function. Injury in turn leads to activation of repair/regeneration-associated mechanisms, including activation of facultative stem/progenitor cells (regulated by TERT, RTEL1) and inflammatory cell recruitment and polarization (influenced by DPP9, TOLLIP, MAD1L1). Failure of normal injury repair leads to fibroblast proliferation and activation, together with epithelial metaplasia, which likely potentiates profibrotic signaling mechanisms, leading to PF progression and the dramatic cellular and architectural remodeling of end-stage fibrosis. Overall, this model provides a synthesis of established roles of PF risk genes on disease biology, highlighting the potential for genes to influence multiple aspects of the disease and serve as potential therapeutic targets to prevent disease progression. Created using BioRender.

Figure 4.

Mapping the spectrum of pulmonary fibrosis phenotypes. This three-dimensional matrix models the complex relationship among genetic/epigenetic/genomic risks and attributes, environmental factors, and clinical manifestations of pulmonary fibrosis (PF) and categorizes PF into unique phenotypes (PF1, PF2, …), informing personalized diagnostics and therapeutic strategies. This framework exemplifies the shift toward precision medicine, melding advanced genomics with established diagnostics to tailor treatment based on a comprehensive understanding of genotype–environment interactions.