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Interstitial lung disease
Original research
MUC5B, telomere length and longitudinal quantitative interstitial lung changes: the MESA Lung Study
  1. John S Kim1,2,
  2. Ani W Manichaikul3,4,
  3. Eric A Hoffman5,
  4. Pallavi Balte2,
  5. Michaela R Anderson2,
  6. Elana J Bernstein2,
  7. Purnema Madahar2,
  8. Elizabeth C Oelsner2,
  9. Steven M Kawut6,7,
  10. Artur Wysoczanski2,
  11. Andrew F Laine8,
  12. Ayodeji Adegunsoye9,
  13. Jennie Z Ma3,
  14. Margaret A Taub10,
  15. Rasika A Mathias10,11,
  16. Stephen S Rich3,4,
  17. Jerome I Rotter12,13,
  18. Imre Noth1,
  19. Christine Kim Garcia2,
  20. R Graham Barr2,14,
  21. Anna J Podolanczuk15
  1. 1Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, USA
  2. 2Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
  3. 3Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, Virginia, USA
  4. 4Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, Virginia, USA
  5. 5Department of Radiology, University of Iowa, Iowa City, Iowa, USA
  6. 6Department of Medicine, Perelman School of Medicine University of Pennsylvania, Philadelphia, Pennsylvania, USA
  7. 7Department of Biostatistics and Epidemiology, Perelman School of Medicine University of Pennsylvania, Philadelphia, Pennsylvania, USA
  8. 8Department of Biomedical Engineering, Columbia University, New York, New York, USA
  9. 9Department of Medicine, University of Chicago, Chicago, Illinois, USA
  10. 10Department of Biostatistics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA
  11. 11Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  12. 12Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California, USA
  13. 13The Institute for Translational Genomics and Population Sciences, The Lundquist Institute, Harbor-UCLA Medical Center, Torrance, California, USA
  14. 14Department of Epidemiology, Columbia University Mailman School of Public Health, New York, New York, USA
  15. 15Division of Pulmonary and Critical Care, Weill Cornell Medical College, New York, New York, USA
  1. Correspondence to Dr John S Kim, Medicine, University of Virginia School of Medicine, Charlottesville, VA 22903, USA; jk6jb{at}virginia.edu

Abstract

Background The MUC5B promoter variant (rs35705950) and telomere length are linked to pulmonary fibrosis and CT-based qualitative assessments of interstitial abnormalities, but their associations with longitudinal quantitative changes of the lung interstitium among community-dwelling adults are unknown.

Methods We used data from participants in the Multi-Ethnic Study of Atherosclerosis with high-attenuation areas (HAAs, Examinations 1–6 (2000–2018)) and MUC5B genotype (n=4552) and telomere length (n=4488) assessments. HAA was defined as the per cent of imaged lung with attenuation of −600 to −250 Hounsfield units. We used linear mixed-effects models to examine associations of MUC5B risk allele (T) and telomere length with longitudinal changes in HAAs. Joint models were used to examine associations of longitudinal changes in HAAs with death and interstitial lung disease (ILD).

Results The MUC5B risk allele (T) was associated with an absolute change in HAAs of 2.60% (95% CI 0.36% to 4.86%) per 10 years overall. This association was stronger among those with a telomere length below an age-adjusted percentile of 5% (p value for interaction=0.008). A 1% increase in HAAs per year was associated with 7% increase in mortality risk (rate ratio (RR)=1.07, 95% CI 1.02 to 1.12) for overall death and 34% increase in ILD (RR=1.34, 95% CI 1.20 to 1.50). Longer baseline telomere length was cross-sectionally associated with less HAAs from baseline scans, but not with longitudinal changes in HAAs.

Conclusions Longitudinal increases in HAAs were associated with the MUC5B risk allele and a higher risk of death and ILD.

  • Imaging/CT MRI etc
  • Interstitial Fibrosis

Data availability statement

Data are available upon reasonable request. Data available upon request if study approved by MESA.

http://dx.doi.org/10.1136/thorax-2021-218139

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    Data availability statement

    Data are available upon reasonable request. Data available upon request if study approved by MESA.

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    Footnotes

    • Twitter @jskim8223, @drdayjee, @AnnaPodolanczuk

    • Contributors Conception and design of the study—JSK, AWM and AP. Data acquisition—AWM, SSR, JR, MT, RM, EAH and RGB. Analysis of the data—JSK and AP. JSK drafted the initial manuscript. All authors contributed to the data interpretation and edited the manuscript for important scientific content. All of the authors agree to be accountable for all aspects of the work in regard to accuracy and integrity. JSK accepts full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish.

    • Funding JSK was supported by the Pulmonary Fibrosis Foundation Scholars Award and grant K23-HL-150301 from the National Heart, Lung and Blood Institute (NHLBI). MRA was supported by grant K23-HL-150280, AP was supported by grant K23-HL-140199, SK was supported by grant K24-HL-103844, and AWM was supported by R01-HL131565 from the NHLBI. EB was supported by grant K23-AR-075112 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. The MESA Lung Study was supported by grants R01-HL077612, R01-HL093081 and RC1-HL100543 from the NHLBI. The MESA Lung Fibrosis Study was funded by grants R01-HL-103676 from the NHLBI. The MESA Project is conducted and supported by the NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420. Also supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Whole-genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) programme was supported by the NHLBI. WGS for 'NHLBI TOPMed: Multi-Ethnic Study of Atherosclerosis (MESA)' (phs001416.v1.p1) was performed at the Broad Institute of MIT and Harvard (3U54HG003067-13S1). Core support including centralised genomic read mapping and genotype calling, along with variant quality metrics and filtering, were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I). Core support including phenotype harmonisation, data management, sample-identity QC and general programme coordination were provided by the TOPMed Data Coordinating Center (R01HL-120393; U01HL-120393; contract HHSN268201800001I). Infrastructure for the CHARGE Consortium is supported in part by the NHLBI grant R01-HL105756.

    • Competing interests EAH is the founder of VIDA Diagnostics, a company that is commercialising lung image analysis software developed, in part, at the University of Iowa. SK reports receipt of grant support from the NIH and Cardiovascular Medical Research and Education Fund and payments/honoria from Children’s Hospital of Philadelphia, University of California, San Francisco, University of Minnesota, PVRI and Stanford University, and support for attending meetings from the Pulmonary Hypertension Association, American Thoracic Society study section, Duke University, World Symposium on Pulmonary Hypertension, PVRI, Children’s Hospital of Philadelphia, University of Miami, Wake Forest University, Aspen Lung Conference and NIH Study Section. SK reports participation on a data safety monitoring board for United Therapeutics and editorial board for the European Respiratory Journal. IN reports receipt of personal fees and other support from Boehringer Ingelheim, HLR/Genentech, Sanofi Aventis, Global Blood Therapeutics and Veracyte outside the scope of this work. CKG reports support from the Department of Defense, Boehringer Ingelheim and AstraZeneca outside the scope of this work. RGB reports receipt of grants from the Alpha-1 Foundation and the COPD Foundation outside the scope of this work. AP reports grant support from the NHLBI and American Lung Association and consulting fees from Regeneron and Boehringer Ingelheim outside the submitted work.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.