2026/05/29 by John S Kim, B. Receveur, D Zhang +29 · 1 voice
Biochemistry, Genetics and Molecular Biology · Medicine · #Epigenetics and DNA Methylation #Frailty in Older Adults #Telomeres, Telomerase, and Senescence
paper · doi:10.1093/ajrccm/aamag259
openalex publication_date 2026/05/29 · openalex created_date 2026/06/10 · openalex updated_date 2026/07/27
RATIONALE: Whole genome sequencing-estimated telomere length (WGS-TL) correlates with directly measured peripheral blood telomere length. However, raw WGS-TL does not account for normal age-related telomere attrition to identify patients with idiopathic pulmonary fibrosis (IPF) with pathologically short telomeres. OBJECTIVES: Determine utility of age-adjusted WGS-TL to identify adults with telomere-related qualifying variants (TRQV) and whether it associates with survival. METHODS: WGS-TL from two samples of community-dwelling adults (MESA) and cigarette smokers (COPDGene) were used to construct an age-adjusted WGS-TL nomogram (n = 9,940) using linear regression models that regressed on raw WGS-TL and adjusted for chronologic age. Using this nomogram, age-adjusted WGS-TL were generated in IPF cases from the Pulmonary Fibrosis Foundation Patient Registry (PFF-PR) (n = 825) to determine diagnostic performance characteristics for identifying TRQV and survival discrimination. MEASUREMENTS AND MAIN RESULTS: There was a higher proportion of IPF patients from the PFF-PR with abnormally short age-adjusted WGS-TL < 10th percentile (28%) compared to MESA (5%) or COPDGene (10%). Among IPF patients, age-adjusted WGS-TL < 10th percentile outperformed raw WGS-TL < 10th percentile at discriminating TRQV (area under the receiver operating curve 0.66 [95% CI 0.60-0.73] vs. 0.62 [95% CI 0.56-0.69]). At both the shorter age-adjusted and raw WGS-TL thresholds, specificity (0.74-0.99) was higher than sensitivity (0.10-0.58). Age-adjusted WGS-TL below 10th percentile was associated with shorter three-year transplant-free survival (HR 1.35, 95% CI 1.05,1.74) but did not improve survival discrimination over clinical variables alone. CONCLUSION: Age-adjusting WGS-TL enables identification of IPF patients with pathologically short telomeres, modestly improves detection of TRQV, and associates with survival.