Observational studyThe Lancet. Respiratory medicine2025
Rare variants and survival of patients with idiopathic pulmonary fibrosis: analysis of a multicentre, observational cohort study with independent validation.
Observational study in The Lancet. Respiratory medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- Performance of age-adjusted whole genome sequencing telomere length in idiopathic pulmonary fibrosis.American journal of respiratory and critical care medicine · 2026Article
- Multi-omics insights into the mechanisms and prognosis of IPF.Genes and environment : the official journal of the Japanese Environmental Mutagen Society · 2026Review
- Polygenic risk and rare variants in endotypes of idiopathic pulmonary fibrosis: a genetic analysis of population-based and case-control cohorts.The Lancet. Respiratory medicine · 2026Article
- Prospective study of fibrosis in the lung endpoints (PROFILE): characteristics of an incident cohort of patients with idiopathic pulmonary fibrosis.BMJ open respiratory research · 2026Observational
- Polygenic risk scores: Navigating the future of precision medicine through economic, ethical, and scientific advancements.iScience · 2026Review
- Age-dependent Genetic Risk in Pulmonary Fibrosis Patients and Relatives.medRxiv : the preprint server for health sciences · 2026Article
- S100A8Frontiers in immunology · 2026Article
- Racial, Ethnic, Sex, and Gender Equity for Inclusive Interstitial Lung Disease Research: An Official American Thoracic Society Research Statement.American journal of respiratory and critical care medicine · 2025Review
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24 authors.
Funding
Abstract
backgroundRare pathogenic variants in telomere-related genes are associated with poorer clinical outcomes in idiopathic pulmonary fibrosis (IPF). We aimed to assess whether rare qualifying variants in monogenic adult-onset pulmonary fibrosis genes are associated with IPF survival. Using polygenic risk scores (PRS), we also evaluated the influence of common IPF risk variants in patients carrying the qualifying variants.
methodsWe identified qualifying variants in telomere and non-telomere genes using whole-genome sequences from individuals clinically diagnosed with IPF and enrolled in the Pulmonary Fibrosis Foundation Patient Registry (PFFPR), a large multicentre, observational cohort study (March 29, 2016 to June 15, 2018, n=888). We also derived a PRS for IPF (PRS-IPF) from known common sentinel IPF variants. The primary outcome was the association between qualifying variants and survival. The secondary outcome was the association between qualifying variants and PRS-IPF. We used logistic regression models adjusted for sex, age at diagnosis, and principal components of genetic heterogeneity to examine the mutual relationship of qualifying variants and PRS-IPF. The association between qualifying variants and PRS-IPF with survival was tested using Cox proportional hazard models adjusted for baseline confounders. Validation of the results was sought in data from an independent multicentre, prospective, observational cohort study of IPF in the UK (PROFILE, May 17, 2010 to Sept 5, 2017, n=472), and results were meta-analysed under a fixed-effects model.
findingsWe included 888 patients from PFFPR and 472 from PROFILE, totalling 1360 participants. In the PFFPR, carriers of qualifying variants in monogenic adult-onset pulmonary fibrosis genes were associated with lower PRS-IPF (odds ratio 1·79 [95% CI 1·15-2·81]; p=0·010) and shorter survival (hazard ratio 1·53 [1·12-2·10]; p=7·33 × 10
interpretationWe found non-additive effects between qualifying variants and common risk variants in IPF survival, suggesting distinct disease subtypes and raising the possibility of using PRS to guide sequencing prioritisation. Assessing the carrier status for qualifying variants and modelling PRS-IPF promises to further contribute to predicting disease progression among patients with IPF.
fundingInstituto de Salud Carlos III; Instituto Tecnológico y de Eenergías Renovables; Cabildo Insular de Tenerife; Fundación DISA; National Heart, Lung, and Blood Institute of the US National Institutes of Health; and UK Medical Research Council.
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