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A novel locus for exertional dyspnoea in childhood asthma

Sanghun Lee, Jessica Ann Lasky-Su, Christoph Lange, Wonji Kim, Preeti Lakshman Kumar, Merry-Lynn N. McDonald, Carlos A. Vaz Fragoso, Cecelia Laurie, Benjamin A. Raby, Juan C. Celedón, Michael H. Cho, Sungho Won, Scott T. Weiss, Julian Hecker on behalf of the NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
European Respiratory Journal 2021 57: 2001224; DOI: 10.1183/13993003.01224-2020
Sanghun Lee
1Dept of Medical Consilience, Division of Medicine, Graduate School, Dankook University, Yongin, South Korea
2Dept of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
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Jessica Ann Lasky-Su
3Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA
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Christoph Lange
2Dept of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
3Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA
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Wonji Kim
3Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA
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Preeti Lakshman Kumar
4Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
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Merry-Lynn N. McDonald
4Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
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  • ORCID record for Merry-Lynn N. McDonald
Carlos A. Vaz Fragoso
5Geriatric Medicine, Yale School of Medicine, New Haven, CT, USA
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Cecelia Laurie
6Dept of Biostatistics, University of Washington, Seattle, WA, USA
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Benjamin A. Raby
3Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA
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Juan C. Celedón
8Division of Pediatric Pulmonary Medicine, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA
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Michael H. Cho
3Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA
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Sungho Won
9Dept of Public Health Science, Seoul National University, Seoul, South Korea
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Scott T. Weiss
3Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA
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Julian Hecker
3Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA
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Abstract

Most children diagnosed with asthma have respiratory symptoms such as cough, dyspnoea and wheezing, which are also important markers of overall respiratory function. A decade of genome-wide association studies (GWAS) have investigated genetic susceptibility to asthma itself, but few have focused on important respiratory symptoms that characterise childhood asthma.

Using whole-genome sequencing (WGS) data for 894 asthmatic trios from a Costa Rican cohort, we performed family-based association tests (FBATs) to assess the association between genetic variants and multiple asthma-relevant respiratory phenotypes: cough, phlegm, wheezing, exertional dyspnoea and exertional chest tightness. We tested whether genome-wide significant associations were replicated in two additional studies: 1) 286 asthmatic trios from the Childhood Asthma Management Program (CAMP), and 2) 2691 African American current or former smokers from the COPDGene study.

In the 894 Costa Rican trios, we identified a genome-wide significant association (p=2.16×10−9) between exertional dyspnoea and the single nucleotide polymorphism (SNP) rs10165869, located on chromosome 2q37.3, that was replicated in the CAMP cohort (p=0.023) with the same direction of association (combined p=3.28×10−10). This association was not found in the African American participants from COPDGene. We also found suggestive evidence for an association between SNP rs10165869 and the atypical chemokine receptor 3 (ACKR3).

Our finding encourages the secondary association analysis of a wider range of phenotypes that characterise respiratory symptoms in other airway diseases/studies.

Abstract

WGS data from a family-based association study suggest that the replicated SNP variant rs10165869 is associated with exertional dyspnoea, likely through the expression of ACKR3 https://bit.ly/3a5ddBd

Footnotes

  • This article has supplementary material available from erj.ersjournals.com

  • Author contributions: S. Lee, C. Lange and J. Hecker conceptualised and designed the project, performed statistical analyses and interpretation, and drafted the manuscript. J.A. Lasky-Su and S.T. Weiss assisted in data preparation and the analyses, as well as manuscript preparation. P.L. Kumar, M-L.N. McDonald and C.A. Vaz Fragoso contributed to the analysis on COPDGene. W. Kim, C. Laurie, B.A. Raby, J.C. Celedón, S. Won and M.H. Cho contributed to the critical revision of the manuscript. All authors contributed to the relevant sections and approved the final manuscript.

  • Conflict of interest: S. Lee has nothing to disclose.

  • Conflict of interest: J.A. Lasky-Su has nothing to disclose.

  • Conflict of interest: C. Lange has nothing to disclose.

  • Conflict of interest: W. Kim has nothing to disclose.

  • Conflict of interest: P.L. Kumar has nothing to disclose.

  • Conflict of interest: M-L.N. McDonald has nothing to disclose.

  • Conflict of interest: C.A. Vaz Fragoso has nothing to disclose.

  • Conflict of interest: C. Laurie has nothing to disclose.

  • Conflict of interest: B.A. Raby has nothing to disclose.

  • Conflict of interest: J.C. Celedon has received research materials from GSK and Merck (inhaled steroids) and Pharmavite (vitamin D and placebo capsules), in order to provide medications free of cost to participants in NIH-funded studies, unrelated to the current work.

  • Conflict of interest: M.H. Cho has nothing to disclose.

  • Conflict of interest: S. Won has nothing to disclose.

  • Conflict of interest: S.T. Weiss reports that he is an author for UpToDate, PI of several NIH grants and an unpaid advisor to Novartis Pharmaceuticals.

  • Conflict of interest: J. Hecker has nothing to disclose.

  • Support statement: This work was supported by the Industrial Core Technology Development Program (20000134) funded by the Ministry of Trade, Industry and Energy (MOTIE, Korea); the Bio-Synergy Research Project (NRF-2017M3A9C4065964) of the Ministry of Science, ICT and Future Planning through the National Research Foundation; Cure Alzheimer's Fund; the National Human Genome Research Institute (R01HG008976, 2U01HG008685); and the National Heart, Lung, and Blood Institute (P01HL132825, U01HL089856, U01HL089897, P01HL120839). Funding information for this article has been deposited with the Crossref Funder Registry.

  • Received April 16, 2020.
  • Accepted July 31, 2020.
  • Copyright ©ERS 2021
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A novel locus for exertional dyspnoea in childhood asthma
Sanghun Lee, Jessica Ann Lasky-Su, Christoph Lange, Wonji Kim, Preeti Lakshman Kumar, Merry-Lynn N. McDonald, Carlos A. Vaz Fragoso, Cecelia Laurie, Benjamin A. Raby, Juan C. Celedón, Michael H. Cho, Sungho Won, Scott T. Weiss, Julian Hecker
European Respiratory Journal Feb 2021, 57 (2) 2001224; DOI: 10.1183/13993003.01224-2020

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A novel locus for exertional dyspnoea in childhood asthma
Sanghun Lee, Jessica Ann Lasky-Su, Christoph Lange, Wonji Kim, Preeti Lakshman Kumar, Merry-Lynn N. McDonald, Carlos A. Vaz Fragoso, Cecelia Laurie, Benjamin A. Raby, Juan C. Celedón, Michael H. Cho, Sungho Won, Scott T. Weiss, Julian Hecker
European Respiratory Journal Feb 2021, 57 (2) 2001224; DOI: 10.1183/13993003.01224-2020
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