You are here

  • Home
  • Archive
  • Volume 72, Issue 5
  • Genetic variants affecting cross-sectional lung function in adults show little or no effect on longitudinal lung function decline

Article Text

Article menu

Download PDFPDF

Chronic obstructive pulmonary disease
Original Article
Genetic variants affecting cross-sectional lung function in adults show little or no effect on longitudinal lung function decline
  1. Catherine John1,
  2. María Soler Artigas1,
  3. Jennie Hui2,3,4,5,
  4. Sune Fallgaard Nielsen6,
  5. Nicholas Rafaels7,
  6. Peter D Paré8,
  7. Nadia N Hansel9,
  8. Nick Shrine1,
  9. Iain Kilty10,
  10. Anders Malarstig11,
  11. Scott A Jelinsky10,
  12. Signe Vedel-Krogh6,
  13. Kathleen Barnes7,
  14. Ian P Hall12,
  15. John Beilby2,3,4,
  16. Arthur W Musk4,5,13,14,
  17. Børge G Nordestgaard6,
  18. Alan James4,14,15,
  19. Louise V Wain1,16,
  20. Martin D Tobin1,16
  1. 1Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester, UK
  2. 2School of Pathology and Laboratory Medicine, The University of Western Australia, Australia
  3. 3PathWest, Department of Health, Government of Western Australia, Perth, WA, Australia
  4. 4Busselton Population Medical Research Institute, Sir Charles Gairdner Hospital, Western Australia, Australia
  5. 5School of Population Health, The University of Western Australia, Australia
  6. 6Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark
  7. 7Center for Personalized Medicine and Biomedical Informatics, School of Medicine, University of Colorado, Anschutz Medical Campus
  8. 8University of British Columbia Centre for Heart Lung Innovation, St Paul's Hospital, Vancouver, British Columbia, Canada
  9. 9Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
  10. 10Pfizer Worldwide Research and Development, Cambridge, Massachusetts, USA
  11. 11Pfizer Worldwide Research and Development, Stockholm, Sweden
  12. 12Division of Respiratory Medicine, Queen's Medical Centre, University of Nottingham, Nottingham, UK
  13. 13Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
  14. 14School of Medicine and Pharmacology, The University of Western Australia, Australia
  15. 15Department of Pulmonary Physiology and Sleep Medicine/West Australian Sleep Disorders Research Institute, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
  16. 16National Institute for Health Research (NIHR) Leicester Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, UK
  1. Correspondence to Dr Catherine John, University of Leicester, Department of Health Sciences, Centre for Medicine, University Road, Leicester LE1 7RH, UK; cj153{at}leicester.ac.uk

Abstract

Background Genome-wide association studies have identified numerous genetic regions that influence cross-sectional lung function. Longitudinal decline in lung function also includes a heritable component but the genetic determinants have yet to be defined.

Objectives We aimed to determine whether regions associated with cross-sectional lung function were also associated with longitudinal decline and to seek novel variants which influence decline.

Methods We analysed genome-wide data from 4167 individuals from the Busselton Health Study cohort, who had undergone spirometry (12 695 observations across eight time points). A mixed model was fitted and weighted risk scores were calculated for the joint effect of 26 known regions on baseline and longitudinal changes in FEV1 and FEV1/FVC. Potential additional regions of interest were identified and followed up in two independent cohorts.

Results The 26 regions previously associated with cross-sectional lung function jointly showed a strong effect on baseline lung function (p=4.44×10−16 for FEV1/FVC) but no effect on longitudinal decline (p=0.160 for FEV1/FVC). This was replicated in an independent cohort. 39 additional regions of interest (48 variants) were identified; these associations were not replicated in two further cohorts.

Conclusions Previously identified genetic variants jointly have a strong effect on cross-sectional lung function in adults but little or no effect on the rate of decline of lung function. It is possible that they influence COPD risk through lung development. Although no genetic variants have yet been associated with lung function decline at stringent genome-wide significance, longitudinal change in lung function is heritable suggesting that there is scope for future discoveries.

  • COPD epidemiology
  • COPD ÀÜ Mechanisms
  • Lung Physiology
  • Respiratory Measurement

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/

https://doi.org/10.1136/thoraxjnl-2016-208448

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    View Full Text

    Footnotes

    • CJ, MSA, LVW and MDT contributed equally.

    • Contributors Project design and management: CJ, MSA, PDP, AM, IPH, JB, AWM, BGN, AJ, LVW and MDT. Phenotype collection and data management: JH, SFN, NR, NNH, SV-K, KB, JB, AWM, BGN and AJ. Genotype collection and data management: JH, SFN, NR, PDP, NNH, IK, AM, SAJ, SV, KB, JB, AWM, BGN and AJ. Data analysis and interpretation: CJ, MSA, SFN, NR, PDP, NNH, NS, IPH, LVW and MDT. Writing: CJ, MSA, SFN, PDP, IPH, AJ, LVW, MDT. CJ, MSA, LVW and MDT contributed equally to this work.

    • Funding This work was supported by the Medical Research Council (G0902313 to MDT) and Pfizer. This paper presents independent research funded partially by the National Institute for Health Research (NIHR). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The Busselton Health Study acknowledges the support of the National Health and Medical Research Council of Australia, the Government of Western Australia (Health Department, Sir Charles Gairdner Hospital, PathWest and Healthway) and Pfizer. The Copenhagen City Heart Study (CCHS) was supported by Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital and the Danish Heart Foundation. The Lung Health Study (LHS) I was supported by the NIH (contract NIH/N01-HR-46002) and genome-wide association genotyping and analysis of LHS was supported by the NIH as part of the Gene Environment Association Studies (GENEVA) (U01HG004738).

    • Competing interests SAJ, AM and IK are employed by Pfizer. IPH reports grants from Pfizer, outside the submitted work. KB reports grants from NIH, during the conduct of the study; personal fees from Up-To-Date, outside the submitted work.

    • Ethics approval The Busselton Health Study genetics study was approved by the University of Western Australia Human Ethics Committee under project numbers RA/4/1/1516 and RA/4/1/2077. The genetic CCHS study was approved by Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark, by Danish ethical committees (the Copenhagen and Frederiksberg committee and the Copenhagen County committee; KF-100.2039/91, KF-01-144/01, H-KF-01-144/01). The LHS protocols were approved by the institutional review board for human studies at each clinical centre and written informed consent was obtained from each participant.

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

    Linked Articles