This Article Full Text Full Text (PDF) Online Supplement All Versions of this Article: 200804-550OCv1 178/7/729    most recent Alert me when this article is cited Alert me if a correction is posted Services Related articles in AJRCCM Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Cronkhite, J. T. Articles by Garcia, C. K. PubMed PubMed Citation Articles by Cronkhite, J. T. Articles by Garcia, C. K.

Telomere Shortening in Familial and Sporadic Pulmonary Fibrosis

¹ 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

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Rare mutations in the genes encoding telomerase are found in patients with familial and sporadic idiopathic interstitial pneumonia and are associated with short telomere lengths. What This Study Adds to the Field Short telomere lengths (<10th percentile) are commonly found in both the familial and sporadic forms of adult-onset pulmonary fibrosis.

 

Related articles in AJRCCM:

Idiopathic Pulmonary Fibrosis: A Disorder of Lung Regeneration?

Victor J. Thannickal and James E. Loyd
AJRCCM 2008 178: 663-665. [Full Text]  

This article has been cited by other articles:

				V. J. Thannickal and J. E. Loyd Idiopathic Pulmonary Fibrosis: A Disorder of Lung Regeneration? Am. J. Respir. Crit. Care Med., October 1, 2008; 178(7): 663 - 665. [Full Text] [PDF]