IDIOPATHIC pulmonary fibrosis is a progressive lung disease in which scar tissue builds up in the lungs for reasons that are not fully understood, leading to breathlessness, cough, and reduced life expectancy. In a large genetic analysis, researchers report that both rare and common genetic variants, including those that influence telomere length, jointly shape the risk of idiopathic pulmonary fibrosis in a context-specific way.
Telomere Length and Idiopathic Pulmonary Fibrosis Subtypes
The team used whole-genome sequencing data from more than 4,600 patients with idiopathic pulmonary fibrosis and over 400,000 controls across three cohorts from the USA and UK. They focused on damaging rare variants in known disease genes, the well-established MUC5B risk variant, and polygenic risk scores (PRS) for idiopathic pulmonary fibrosis and telomere length. Between 23–43% of patients either carried rare damaging variants or had very short telomeres, under the tenth percentile, highlighting substantial genetic heterogeneity within the disease.
Importantly, a higher PRS for shorter telomere length and an idiopathic pulmonary fibrosis PRS (excluding MUC5B) each showed similar, moderate associations with disease diagnosis across all cohorts, with odds ratios ranging from 1.2–1.6. The impact of telomere length PRS was greatest in patients without rare variants but with particularly short telomeres, suggesting that common telomere-related variants may be especially relevant in this subgroup.
Polygenic Risk as a Clinical Tool
When clinical characteristics were combined with rare variants, the MUC5B variant, idiopathic pulmonary fibrosis polygenic risk and telomere length polygenic risk, prediction of idiopathic pulmonary fibrosis was strongest, with an area under the curve close to 0.9 in two cohorts and 0.77 in the UK Biobank. Rare and common variants together contributed to overall genetic liability, with the telomere length score explaining up to 13% of the genetic risk accounted for in each dataset.
For clinicians, these findings support a move towards endotyping idiopathic pulmonary fibrosis based on both rare and polygenic variation, particularly telomere-associated risk. While not ready for routine practice, polygenic scores for telomere length could, in time, help refine risk stratification, guide surveillance, and identify patients more likely to follow a telomere-driven disease course, paving the way for more personalised management of this complex lung condition.
Reference
Duckworth A et al. Polygenic risk and rare variants in endotypes of idiopathic pulmonary fibrosis: a genetic analysis of population-based and case–control cohorts. Lancet Respir Med. 2026; DOI:10.1016/S2213-2600(25)00405-9.
