Gene Variants Linked With Survival Outcomes in IPF

A new report suggests that rare qualifying variants on both telomere and non-telomere genes have an impact on patient survival in idiopathic pulmonary fibrosis (IPF). The study, which was published in The Lancet Respiratory Medicine, also shows that such variants have nonadditive effects on common IPF risk variants, suggesting that polygenic risk scores (PRS-IPF) may play an important role in guiding patient care.1

People with IPF typically only survive between 3 and 5 years after their diagnosis, in part due to the aggressive nature of IPF and in part due to a lack of understanding about the causes of variations in the clinical course of the disease.

Corresponding author Carlos Flores, PhD, of the Health Research Institute of the Canary Islands, in Spain, explained along with colleagues that recent genetic studies have helped identify both rare and common genetic variants at play in the pathogenesis of IPF. Those findings have helped carve out a role for genetic testing in determining disease prognosis, they said.2

Flores and colleagues said genome-wide association studies (GWAS) have led to the identification of individual genetic risk factors for IPF. Yet, they said there has not yet been extensive research looking into the effect of telomere and nontelomere genetic variants on survival. They said more work is also needed to understand the aggregate effect of rare and common IPF-related variants on patient outcomes.

Genetic variants have nonadditive effects on common IPF risk variants. | Image Credit: © CrazyJuke - stock.adobe.com

In the new study, the investigators used whole-genome sequencing from patients with IPF to assess the prevalence of qualifying variants in monogenic adult-onset pulmonary fibrosis genes and looked for potential associations between those qualifying variants, PRS-IPF, and patient survival.

The investigators enrolled 1360 patients from 2 patient registries in their study. The participants had a mean age of 71 years and three-quarters were male. One database, with 888 patients, was used to identify patients with qualifying variants in telomere and nontelomere genes using whole-genome sequences (WGS). The second database of 472 patients was used as a validation cohort.

In the first dataset, the investigators found that patients who were carriers of qualifying variants in monogenic adult-onset pulmonary fibrosis genes were more likely to have low PRS-IPF scores (OR, 1.79; 95% C], 1.15-2.81; P = .010). Those patients also had shorter survival (HR, 1.53; 95% CI, 1.12-2.10; P = 7.33 x 10–3). Patients with the lowest PRS-IPF scores also had worse survival, the investigators found (HR, 1.61; 95% CI, 1.25-2.07; P = 1.87 x 10–4). The authors said their findings were validated in the second cohort.

In addition to finding that carriers of certain telomere and nontelomere variants are at an increased risk of shorter survival, the investigators said their findings also suggest that such genetic variants have nonadditive effects to common IPF risk variants.

“This result indicates that the interplay between these rare and common variants define distinct genetic subtypes of IPF,” they wrote.

The authors cited limitations to their findings. They noted that their study did not include all of the genes involved in IPF risk, such as ABCA3 or NOP10. Their analysis also did not account for extrapulmonary manifestations or the phenomenon of genetic anticipation, they said.

The authors said such limitations may indicate additional variability that is not captured by their main model.

Still, Flores and colleagues concluded that their findings highlight the potential value of identifying qualifying variants in telomere and nontelomere genes associated with monogenic forms of pulmonary fibrosis in clinical practice.

References

1. Alonso-González A, Jáspez D, Lorenzo-Salazar JM, 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;13(6):495-504. doi:10.1016/S2213-2600(25)00045-1
2. Raghu G, Remy-Jardin M, Richeldi L, et al. Idiopathic pulmonary fibrosis (an update) and progressive pulmonary fibrosis in adults: an official ATS/ERS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med. 2022;205(9):e18-e47. doi:10.1164/rccm.202202-0399ST