Daijiworld Media Network - Mumbai
Mumbai, Feb 4: A recent study published in The Lancet Respiratory Medicine has suggested that short telomere length may increase the risk of idiopathic pulmonary fibrosis (IPF) even in patients who do not carry rare damaging genetic variants, offering fresh insight into the complex genetic nature of the progressive lung disease.
Idiopathic pulmonary fibrosis is a chronic and worsening interstitial lung disease with no known origin or cure. It affects nearly three million people globally, significantly impacting patients, families and healthcare systems. While earlier studies have identified both rare and common genetic variants linked to IPF, researchers have increasingly focused on telomere biology, as unusually short telomeres can lead to premature cell ageing, malfunction or cell death.
Telomere maintenance genes such as TERT, TER and RTEL1 are known to contribute to telomere shortening, and scientists believe this may play a role in IPF when combined with broader polygenic risk.
Unlike previous research that examined rare variants or polygenic risk separately, this study assessed both together to determine whether they are causally linked to IPF progression.
The study analysed data from a Columbia University case-control cohort consisting of 777 IPF patients and 2,905 controls, recruited between 2003 and 2019. Researchers further validated their findings using whole-genome sequencing data from TOPMed and the UK Biobank.
The TOPMed dataset included 1,148 IPF cases and 5,202 controls, while the UK Biobank cohort included 2,739 IPF cases and 395,331 controls. Across all cohorts, the median age ranged from 64 to 67 years, with the majority being male and of European ancestry.
Researchers identified rare damaging variants in IPF-associated genes and calculated polygenic risk scores (PRS) for both IPF and telomere length, using independent genome-wide association study data.
They identified 16 SNPs associated with IPF and 190 SNPs linked to telomere length, and found that the distribution of PRS differed significantly between IPF patients and control groups in all cohorts.
In the Columbia cohort, 12% of IPF patients carried rare damaging variants — a similar proportion to TOPMed, though lower in the UK Biobank.
The study found strong independent associations between IPF risk and:
• Rare damaging variants
• The MUC5B rs35705950 promoter polymorphism
• IPF PRS excluding MUC5B
• Telomere length PRS
Importantly, researchers noted that telomere length PRS was associated with increased IPF risk in both rare variant carriers and noncarriers, suggesting telomere shortening remains a key driver even when rare genetic mutations are absent.
Risk was highest among individuals whose telomere length fell below the 10th percentile, while those with telomere length above the median showed the lowest risk.
The authors said their findings indicate multiple IPF “endotypes” may exist, with telomere shortening being a shared feature, but with distinct genetic influences behind it.
They noted that patients with unexplained short telomeres may also carry additional polygenic risk factors, underscoring the need for better genetic classification and personalised approaches in future research and treatment.
While the study acknowledged limitations — including limited adjustment for environmental risk factors and reduced applicability of polygenic scores to non-European populations — researchers said accounting for both rare and common genetic influences could improve disease prediction and better explain IPF heterogeneity.