Polygenic Risk Score May Improve Idiopathic Pulmonary Fibrosis Risk Prediction

Researchers found that a polygenic risk score (PRS) was associated with the risk of idiopathic pulmonary fibrosis (IPF), supporting its potential as a future tool for identifying individuals at increased risk.¹

IPF is a rare and difficult disease to diagnose due to overlapping symptoms with other interstitial lung diseases (ILD) and because its cause is unknown. Previous studies have shown that genetic variants contribute to both sporadic and familial IPF risk, and factors such as telomere length have also been associated with disease susceptibility and progression. However, this study, as one of the largest real-world evaluations, aimed at determining whether PRS may be associated with IPF diagnosis, mortality, or lung transplant among patients with IPF. The findings suggest that PRS could serve as a tool to provide insights into IPF disease risk in future studies and in clinical practice, as there is currently no single diagnostic test or biomarker that can definitively confirm IPF.¹

The study, led by Mayo Clinic and Brigham and Women’s Hospital, analyzed data from 572,528 patients across Mass General Brigham Biobank (MGBB) (37,709), Mayo Clinic BioBank (MCBB) (44,195), Mayo Clinic’s Tapestry Cohort (43,202), and the UK Biobank (447,422).^1,2

Researchers evaluated 3 increasingly stringent definitions of IPF using International Classification of Diseases, Ninth Revision (ICD-9) and ICD-10 billing codes to assess whether the PRS remained associated with disease regardless of how IPF was defined. IPF broad defined all individuals with the presence of any other interstitial pulmonary disease with fibrosis. IPF narrow defined all patients in the IPF broad category but excluded those with co-occurring ICD codes that suggested secondary or alternative etiologies for fibrosis. IPF specific defined ICD-10 and ICD-9 codes specifically for IPF.¹

The PRS incorporated the MUC5B rs35705950-T risk allele together with a normalized genome-wide PRS generated using the lassosum method. Individuals with a high PRS were associated with ILD and IPF diagnoses across all cohorts.

The prevalence of ILD and IPF diagnoses varied across cohorts. Specifically, a broad IPF diagnosis varied from a minimum of 2742 in the UK Biobank to a maximum of 2879 in the Mayo Clinic Biobank.

High-risk IPF was associated with increased odds of ILD 1.36 (95% CI, 1.07-1.77), IPF broad 1.53 (95% CI, 1.18-1.99), IPF narrow 1.39 (95% CI, 1.03-1.88), and IPF specific 2.88 (95% CI, 2.41-3.44), when compared with other individuals.

The study also evaluated the factors associated with a composite end point of all-cause mortality or lung transplant. Each one-standard-deviation increase in PRS was significantly associated with increased hazards of the composite endpoints. This pattern was observed consistently in the UKBB and MCBB cohorts.

IPF broad demonstrated an increased hazard of the composite endpoint (HR 1.09, 95% CI, 1.05-1.13) per standard deviation of the PRS, replicating in all cohorts except for the Tapestry cohort. IPF narrow demonstrated an increased hazard of the composite endpoint (random effects HR 1.12, 95% CI, 1.05-1.20) per standard deviation of the PRS in all cohorts except MGBB.

The study was limited by its reliance on billing codes, which could lead to misclassification or incomplete capture of cases. Chest computed tomography scans, detailed clinical histories, or physician diagnostic confidence, which could also affect case identification. Lastly, all participants were of European descent, limiting the generalizability of findings to other patient populations.

“Polygenic risk scores add a new layer of biological insight into the prediction of pulmonary fibrosis and mortality outcomes, bringing us closer to a future where diagnosis, prognosis and treatment are informed by each patient’s unique molecular signatures,” said Victor Ortega, MD, PhD, a pulmonologist and associate director of Mayo Clinic’s Center for Individualized Medicine in Arizona, in a statement.²

References

1. Karla SS, Grilli CB, Coombes BJ, et al. Association of a polygenic risk score with diagnosis and outcomes in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2026. doi:10.1093/ajrccm/aamag271

2. Researchers chart a genetic path to diagnosing pulmonary fibrosis and predicting outcomes. Mayo Clinic. News release. July 7, 2026. Accessed July 8, 2026. https://www.newswise.com/articles/researchers-chart-a-genetic-path-to-diagnosing-pulmonary-fibrosis-and-predicting-outcomes