NEW research has revealed that rare genetic variants and common polygenic risk scores independently influence survival in idiopathic pulmonary fibrosis (IPF), highlighting their potential in guiding personalised care for patients with this progressive lung disease.
Researchers analysed whole-genome sequences from 888 individuals enrolled in the Pulmonary Fibrosis Foundation Patient Registry (PFFPR) between 2016 and 2018, focusing on rare qualifying variants in telomere-related and other monogenic genes associated with adult-onset pulmonary fibrosis. A polygenic risk score for IPF (PRS-IPF) was also calculated based on known common genetic variants. The association of these genetic factors with survival was evaluated using Cox proportional hazard models, adjusting for sex, age at diagnosis, and genetic ancestry. Validation of findings was performed using data from the UK-based PROFILE cohort (n=472), with results combined in a fixed-effects meta-analysis.
In the PFFPR cohort, carriers of qualifying variants in monogenic adult-onset pulmonary fibrosis genes had significantly lower PRS-IPF (odds ratio: 1.79, 95% CI: 1.15–2.81; P=0.010) and reduced survival (hazard ratio: 1.53, 95% CI: 1.12–2.10; P=0.00733). Moreover, individuals with the lowest PRS-IPF also showed worse survival outcomes (hazard ratio: 1.61, 95% CI: 1.25–2.07; P=0.000187), suggesting an independent contribution of common and rare genetic factors. These findings were replicated in the PROFILE cohort, confirming the consistency of the genetic associations across populations.
The study indicates that rare variants and polygenic risk scores interact in a non-additive manner, likely representing distinct IPF subtypes with differing prognoses. Incorporating both rare variant screening and polygenic modelling may enhance risk stratification and clinical decision-making in IPF management.
Reference
Alonso-González A et al. Rare variants and survival of patients with idiopathic pulmonary fibrosis: analysis of a multicentre, observational cohort study with independent validation. Lancet Respir Med. 2025; DOI:10.1016/S2213-2600(25)00045-1.
