Telomere Length and Polygenic Risk Shape Endotypes in Idiopathic Pulmonary Fibrosis

Telomere length may contribute to disease risk in patients with idiopathic pulmonary fibrosis (IPF) who are also noncarriers of rare genetic variants, according to a recent study published in The Lancet Respiratory Medicine.1

IPF is a chronic, progressive fibrosing interstitial lung disease (ILD) for which there is no known origin or cure. It affects nearly 3 million people worldwide and has a significant impact on patients’ quality of life, families, and the health care system.1,2 Prior research has aimed to find a cause or association for IPF in addition to ongoing clinical trials assessing the efficacy of targeted therapies. Currently, numerous studies have identified rare and common genetic variants that influence a patient’s risk of developing IPF, particularly those that affect telomere biology. Telomeres, when too short, can result in premature cell aging, malfunction, or death. Telomere maintenance genes, TERT, TER, and RTEL1, cause telomere shortening, which researchers suggest may be associated with IPF when combined with polygenic risk.1

A Lancet Respiratory Medicine study links telomere shortening and polygenic risk to distinct genetic endotypes in IPF. | Image Credit: lucadp-Adobestockjpeg

How Telomere Shortening and Polygenic Risk Contribute to IPF

This study, unlike previous studies, aimed to assess both rare damaging variants and polygenic risk together to determine whether their presence is causally related to IPF disease progression.

There were 777 patients with IPF and 2905 non-IPF control patients in this study, recruited between April 2003 and June 19, 2019, whose data were sequenced at Columbia University. In addition to the whole-genome sequencing (WGS) data from the discovery case-control cohort sequenced at Columbia University, the researchers used WGS data from Trans-Omics for Precision Medicine (TOPMed) and the UK Biobank to validate their findings.

Using these data, the study authors identified rare damaging variants in disease-associated genes and computed polygenic risk scores (PRS) for IPF and telomere length. PRS were computed using independent genome-wide association study (GWAS) data to generate weighted scores. In this process, they identified 16 single-nucleotide polymorphisms (SNPs) related to IPF and 190 SNPs related to telomere length.

Researchers compared their findings to those of the UK Biobank and TOPMed cohorts. In the TOPMed cohort, there were 1148 individuals with IPF and 5202 non-IPF control patients. In the UK Biobank cohort, there were 2739 patients with IPF and 395,331 non-IPF control patients. The median ages of all 3 cohorts was 64 to 67 years; furthermore, 61% to 72% of patients were male, and 84% to 96% were of European ancestry.

Independent Effects of Rare Variants, MUC5B, and Polygenic Risk Scores

In the Columbia cohort, 94 (12%) of 777 patients were carriers of rare damaging variants in the IPF-associated genes compared with 143 (12%) of 1148 in the TOPMed cohort and 108 (4%) in the UK Biobank cohort.

Although telomere length data were unavailable for the Columbia cohort, among the TOPMed and UK Biobank cohorts, rare variant carriers and noncarriers with a telomere length below the 10th percentile constituted 23% to 43% of those with IPF.

However, there was a significant difference in PRS distribution between individuals with IPF and those in the control group across all 3 cohorts (all P < .0001). Researchers found independent associations between IPF risk and rare variants (OR, 12.01; 95% CI, 7.54-19.52; P = 1.0×10–24), the single MUC5B rs35705950 promoter polymorphism (OR, 2.00; 95% CI, 1.85-2.15; P = 4.0×10–72), the IPF PRS excluding MUC5B (OR, 1.60; 95% CI, 1.44-1.77; P = 9.4×10–19), and telomere length PRS (OR, 1.63; 95% CI, 1.47-1.81; P = 5.5×10–21).

Similar independent associations were observed in the UK Biobank and TOPMed cohorts.

Because the polygenic scores exerted independent effects, their associations with IPF risk were examined across genetic endotypes in the Columbia cohort. The MUC5B rs35705950 polymorphism was consistently associated with IPF across all endotypes (OR, 2.02; 95% CI, 1.88-2.17), despite a lower prevalence among carriers of rare variants.

The IPF PRS excluding MUC5B was associated with IPF risk among noncarriers of rare variants compared with controls (OR, 1.69; 95% CI, 1.54-1.86), but showed no meaningful association among rare variant carriers (OR, 1.23; 95% CI, 1.00-1.51).

In contrast, the telomere length PRS was associated with IPF risk in both rare variant carriers (OR, 1.63; 95% CI, 1.33-1.99) and noncarriers (OR, 1.58; 95% CI, 1.44-1.73). Risk increased with shorter telomere length, with the highest odds observed in individuals with telomeres below the 10th percentile (OR, 2.02; 95% CI, 1.76-2.33) and the lowest odds in those above the 50th percentile (OR, 1.23; 95% CI, 1.06-1.44).

Implications for IPF Endotypes and Precision Medicine

“Our focus on telomere length indicated that there were multiple endotypes with shared telomere shortening but distinct genetic influences,” the study authors wrote. “Unlike those carrying rare variants in telomere-related genes, patients with IPF who have unexplained short telomere length are also enriched in other IPF-related polygenic risk factors.”

The use of clinical phenotyping varied across cohorts, limited adjustment for key nongenetic risk factors (eg, smoking and environmental exposures), and prevented definitive assessments of gene-environment interactions. Because IPF GWAS have largely included individuals of European ancestry, polygenic scores cannot be generalized across other ancestries. The study was also limited by potential enrollment and diagnostic biases in the UK Biobank cohort, limited power to assess gene-specific effects among rare variant carriers, and the need for further work to translate genetic endotypes into routine clinical practice.

“Polygenic background and rare variation contribute to the genetic risk of IPF both independently and in tandem. Although attenuated, polygenic modifiers of disease risk exist even in patients with IPF who carry rare damaging variants,” the study authors concluded. “Accounting for these novel genetic risk factors both improves disease prediction and explains additional genetic liability. Taken together, our findings underscore the importance of understanding IPF heterogeneity from rare and common genetic influences that might be relevant for future studies.”

References

1. Duckworth A, Jackson L, Green H, 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. Published online January 27, 2026. doi:10.1016/S2213-2600(25)00405-9

2. Glassberg MK. Overview of idiopathic pulmonary fibrosis, evidence-based guidelines, and recent developments in the treatment landscape. AJMC. July 19, 2019. Accessed February 3, 2026. https://www.ajmc.com/view/overview-idiopathic-pulmonary-fibrosis-evidence-based-guidelines-recent-developments-treatment-landscape