The Prognostic and Predictive Impact of Telomere Length in Fibrotic Interstitial Lung Disease

/ABSTRACT The interstitial lung diseases (ILD) are a group of incurable fibrotic and inflammatory disorders that confer substantial mortality risk through progressive loss of lung function. The ILDs are categorized into discrete diagnostic subtypes to inform clinical management. However, diagnostic categorization is imprecise and is unable to reliably identify individual patients at high risk for rapid progression or poor survival. Leukocyte telomere length is an emerging prognostic biomarker that consistently informs individual progression and mortality risk. In addition, a recently discovered pharmacogenomic interaction between short leukocyte telomere length and immunosuppressant medications suggests that leukocyte telomere length is also a predictive biomarker that can aid in ILD treatment selection. This proposal seeks to leverage a multicenter cohort of >4000 ILD patients to outline relevant information gained from clinical leukocyte telomere length measurement across the spectrum of fibrotic ILDs. In Aim 1, we will quantify the age-adjusted leukocyte telomere length threshold that best informs differential progression and mortality risk. Using these thresholds, we will then calculate performance characteristics to provide clinicians with discriminatory power of leukocyte telomere length in forecasting outcome risk to inform clinical decision making. In Aim 2, we will study treatment naïve fibrotic ILD patients to quantify the effect of age-adjusted leukocyte telomere length on incident progression and near-term mortality while accounting for ILD treatment effects. This aim will quantify the independent impact leukocyte telomere length and treatment selection on ILD outcome risks. In Aim 3, we will create a risk prediction model anchored on leukocyte telomere length that informs both near-term progression and mortality risk. We will then incorporate subsequent treatment exposure to calculate the change in risk profile conferred by specific treatment selection. Successful completion of the proposed aims will create a tractable predictive tool integrating a blood biopsy with clinic-radiologic features that informs personalized ILD management without constraints of the current, imprecise ILD diagnostic categorization. In addition, results from these studies will form the foundation for future prospective cohort studies and stratified clinical trials to validate the ability of leukocyte telomere length to function as a prognostic and predictive biomarker and usher in the era of precision medicine in fibrotic ILD. Project Number: 5R01HL176839-02 | Fiscal Year: 2026 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Chad Newton | Institution: UT SOUTHWESTERN MEDICAL CENTER, DALLAS, TX | Award Amount: $704,444 | Activity Code: R01 | Study Section: Cardiovascular and Respiratory Diseases Study Section[CRD] View on NIH RePORTER: https://reporter.nih.gov/project-details/5R01HL17683902