Genetics of Pulmonary Fibrosis: From Familial Predisposition to Clinical Application

Background. Pulmonary fibrosis encompasses a heterogeneous group of interstitial lung diseases (ILDs) characterized by progressive remodelling and scarring of the lung parenchyma. Although environmental and clinical factors contribute substantially to disease development, increasing evidence indicates that genetic susceptibility plays a central role in determining individual risk, disease phenotype, age at onset, and clinical outcome. Methods and objectives. This narrative review provides an interpretative overview of the genetic mechanisms underlying pulmonary fibrosis, focusing on familial pulmonary fibrosis (FPF), major susceptibility genes, and the clinical implications of genetic testing. Results. Familial pulmonary fibrosis, generally defined by the occurrence of pulmonary fibrosis in at least two relatives within the third degree of relationship, represents approximately 20% of pulmonary fibrosis cases and is frequently characterized by earlier disease onset and a more aggressive clinical course than sporadic disease. The genetic architecture of pulmonary fibrosis is complex, involving both common and rare genetic variants, with telomere maintenance and mucin regulation representing key biological pathways underlying disease susceptibility, although identifiable causal variants are found in only approximately 25% of affected families. In parallel, common genetic variants, particularly the MUC5B promoter variant rs35705950 and variants in TOLLIP, contribute to disease susceptibility and may influence disease progression and treatment response. Conclusion. The increasing availability of genetic testing has important implications for diagnosis, family screening, prognosis and potentially treatment selection. Integrating genetic sequencing with telomere length assessment may provide complementary information and contribute to a more individualized approach to patients with pulmonary fibrosis.