Published ahead of print on July 17, 2008, doi:10.1164/rccm.200804-550OC
© 2008 American Thoracic Society doi: 10.1164/rccm.200804-550OC
Telomere Shortening in Familial and Sporadic Pulmonary Fibrosis1 Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas; 2 Division of Pulmonary and Critical Care Medicine, University of Washington Medical Center, Seattle, Washington; and 3 Division of Pulmonary and Critical Care Medicine, University of Texas Southwestern Medical Center, Dallas, Texas Correspondence and requests for reprints should be addressed to Christine Kim Garcia, M.D., Ph.D., University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8591. E-mail: christine.garcia{at}utsouthwestern.edu Rationale: Heterozygous mutations in the coding regions of the telomerase genes, TERT and TERC, have been found in familial and sporadic cases of idiopathic interstitial pneumonia. All affected patients with mutations have short telomeres. Objectives: To test whether telomere shortening is a frequent mechanism underlying pulmonary fibrosis, we have characterized telomere lengths in subjects with familial or sporadic disease who do not have coding mutations in TERT or TERC. Methods: Using a modified Southern blot assay, the telomerase restriction fragment length method, and a quantitative polymerase chain reaction assay we have measured telomere lengths of genomic DNA isolated from circulating leukocytes from normal control subjects and subjects with pulmonary fibrosis. Measurements and Main Results: All affected patients with telomerase mutations, including case subjects heterozygous for newly reported mutations in TERT, have short telomere lengths. A significantly higher proportion of probands with familial pulmonary fibrosis (24%) and sporadic case subjects (23%) in which no coding mutation in TERT or TERC was found had telomere lengths less than the 10th percentile when compared with control subjects (P = 2.6 x 10–8). Pulmonary fibrosis affectation status was significantly associated with telomerase restriction fragment lengths, even after controlling for age, sex, and ethnicity (P = 6.1 x 10–11). Overall, 25% of sporadic cases and 37% of familial cases of pulmonary fibrosis had telomere lengths less than the 10th percentile. Conclusions: A significant fraction of individuals with pulmonary fibrosis have short telomere lengths that cannot be explained by coding mutations in telomerase. Telomere shortening of circulating leukocytes may be a marker for an increased predisposition toward the development of this age-associated disease.
Key Words: idiopathic pulmonary fibrosis • pulmonary fibrosis • telomere length • aging • interstitial lung disease
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