Genetic variants affecting cross-sectional lung function in adults show little or no effect on longitudinal lung function decline

Catherine John; María Soler Artigas; Jennie Hui; Sune Fallgaard Nielsen; Nicholas Rafaels; Peter D Paré; Nadia N Hansel; Nick Shrine; Iain Kilty; Anders Malarstig; Scott A Jelinsky; Signe Vedel-Krogh; Kathleen Barnes; Ian P Hall; John Beilby; Arthur W Musk; Børge G Nordestgaard; Alan James; Louise V Wain; Martin D Tobin

doi:10.1136/thoraxjnl-2016-208448

Genetic variants affecting cross-sectional lung function in adults show little or no effect on longitudinal lung function decline

Thorax. 2017 May;72(5):400-408. doi: 10.1136/thoraxjnl-2016-208448. Epub 2017 Feb 7.

Authors

Catherine John¹, María Soler Artigas¹, Jennie Hui^{2

3

4

5}, Sune Fallgaard Nielsen⁶, Nicholas Rafaels⁷, Peter D Paré⁸, Nadia N Hansel⁹, Nick Shrine¹, Iain Kilty¹⁰, Anders Malarstig¹¹, Scott A Jelinsky¹⁰, Signe Vedel-Krogh⁶, Kathleen Barnes⁷, Ian P Hall¹², John Beilby^{2

3

4}, Arthur W Musk^{4

5

13

14}, Børge G Nordestgaard⁶, Alan James^{4

14

15}, Louise V Wain^{1

16}, Martin D Tobin^{1

16}

Affiliations

¹ Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester, UK.
² School of Pathology and Laboratory Medicine, The University of Western Australia, Australia.
³ PathWest, Department of Health, Government of Western Australia, Perth, WA, Australia.
⁴ Busselton Population Medical Research Institute, Sir Charles Gairdner Hospital, Western Australia, Australia.
⁵ School of Population Health, The University of Western Australia, Australia.
⁶ Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark.
⁷ Center for Personalized Medicine and Biomedical Informatics, School of Medicine, University of Colorado, Anschutz Medical Campus.
⁸ University of British Columbia Centre for Heart Lung Innovation, St Paul's Hospital, Vancouver, British Columbia, Canada.
⁹ Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
¹⁰ Pfizer Worldwide Research and Development, Cambridge, Massachusetts, USA.
¹¹ Pfizer Worldwide Research and Development, Stockholm, Sweden.
¹² Division of Respiratory Medicine, Queen's Medical Centre, University of Nottingham, Nottingham, UK.
¹³ Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
¹⁴ School of Medicine and Pharmacology, The University of Western Australia, Australia.
¹⁵ Department of Pulmonary Physiology and Sleep Medicine/West Australian Sleep Disorders Research Institute, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
¹⁶ National Institute for Health Research (NIHR) Leicester Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, 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.

Keywords: COPD epidemiology; COPD ÀÜ Mechanisms; Lung Physiology; Respiratory Measurement.

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Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Cross-Sectional Studies
Disease Progression
Female
Genetic Predisposition to Disease
Genetic Variation*
Genome-Wide Association Study
Genotype
Humans
Longitudinal Studies
Male
Middle Aged
Pulmonary Disease, Chronic Obstructive / genetics*
Pulmonary Disease, Chronic Obstructive / physiopathology*
Respiration / genetics*
Respiratory Function Tests
Risk Assessment
Risk Factors
Spirometry
Time Factors
Western Australia

Abstract

Publication types

MeSH terms

Grants and funding