Telomere Length and Genetic Variant Associations with Interstitial Lung Disease Progression and Survival
- Chad A. Newton1,*,
- Justin M. Oldham2,
- Brett Ley3,
- Vikram Anand1,
- Ayodeji Adegunsoye4,
- Gabrielle Liu3,
- Kiran Batra5,
- Jose Torrealba6,
- Julia Kozlitina7,
- Craig Glazer5,
- Mary E. Strek4,
- Paul J. Wolters3,
- Imre Noth8 and
- Christine Kim Garcia1,7
- 1Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX
- 2Department of Internal Medicine, University of California at Davis, Davis, CA
- 3Department of Medicine, University of California San Francisco, San Francisco, CA
- 4Department of Medicine, University of Chicago, Chicago, IL
- 5Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX
- 6Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX
- 7Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX
- 8Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA
- *Chad A. Newton, MD, 5323 Harry Hines Blvd, Dallas, TX 75390-8558. E-mail: chad.newton{at}utsouthwestern.edu
Abstract
Leukocyte telomere length (LTL), MUC5B rs35705950, and TOLLIP rs5743890 have been associated with idiopathic pulmonary fibrosis (IPF). In this observational cohort study, we assessed the associations between these genomic markers and outcomes of survival and rate of disease progression in patients with interstitial pneumonia with autoimmune features (IPAF, n=250) and connective tissue disease-associated interstitial lung disease (CTD-ILD, n=248). IPF (n=499) was used as a comparator.
LTL of IPAF and CTD-ILD patients (mean age-adjusted log-transformed T/S of −0.05, [sd 0.29] and −0.04 [0.25], respectively) are longer than IPF (−0.17 [0.32]). For IPAF, LTL <10th percentile is associated with faster lung function decline compared to LTL ≥10th percentile (−6.43%/year versus −0.86%/year, p<0.0001) and worse transplant-free survival (HR 2.97 [95% CI 1.70–5.20], p=0.00014). The MUC5B rs35705950 minor allele frequency is greater for IPAF (23.2 [95% CI 18.8–28.2], p<0.0001) than controls and is associated with worse transplant-free IPAF survival (HR 1.92, [95% CI 1.18–3.13], p=0.0091). Rheumatoid arthritis-associated ILD (RA-ILD) has shorter LTL than non-RA CTD-ILD (−0.14 [sd 0.27] versus −0.01 [0.23], p=0.00055) and higher MUC5B minor allele frequency (34.6 [95% CI 24.4–46.3] versus 14.1 [9.8–20.0], p=0.00025). Neither LTL nor MUC5B are associated with transplant-free CTD-ILD survival.
LTL and MUC5B minor allele frequency have different associations with lung function progression and survival for IPAF and CTD-ILD.
Footnotes
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Conflict of interest: Dr. Newton reports no relevant conflicts of interest.
Conflict of interest: Dr. Oldham reports grants from NHLBI, personal fees from Genentech, personal fees from BI, outside the submitted work.
Conflict of interest: Dr. Ley has nothing to disclose.
Conflict of interest: Dr. Anand has nothing to disclose.
Conflict of interest: Dr. Adegunsoye reports having received speaking fees and honoraria for advisory boards with Boehringer Ingelheim related to IPF within the last 12 months.
Conflict of interest: Dr. Liu has nothing to disclose.
Conflict of interest: Dr. Batra has nothing to disclose.
Conflict of interest: Dr. Torrealba reports personal fees from Roche – Ventana, personal fees from AbbVie, outside the submitted work.
Conflict of interest: Dr. Kozlitina has nothing to disclose.
Conflict of interest: Dr. Glaser reports and I am on the speaker's bureau for genentech there is no discussion of therapy in this paper but in the interest of full discloser I wanted to include.
Conflict of interest: Dr. Strek reports grants from Boehringer-Ingelheim, grants from Genentech-Roche, grants from Gilead, grants from MedImmune, personal fees from Boehringer-Ingelheim, outside the submitted work.
Conflict of interest: Dr. Wolters reports grants from medimmune, grants from Genentech, personal fees from Roche, personal fees from Boehringer Ingelheim, outside the submitted work.
Conflict of interest: Dr. North reports personal fees from Boehringer Ingelheim, personal fees from Genentech, personal fees from Sanofi Aventis, personal fees from Global Blood Therapeutics, outside the submitted work; In addition, Dr. Noth has a patent TOLLIP and IPF pharmacogenomics pending.
Conflict of interest: Dr. Garcia has no relevant conflicts of interest.
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- Copyright ©ERS 2019