Impact of non-linear smoking effects on the identification of gene-by-smoking interactions in COPD genetics studies

Peter J. Castaldi, D. L. Demeo, C. P. Hersh, D. A. Lomas, I. C. Soerheim, A. Gulsvik, P. Bakke, S. Rennard, Peter Pare, J. Vestbo, E. K. Silverman, Alvar Agusti, Peter Calverley, Claudio F. Donner, Robert D. Levy, David Lomas, Barry J. Make, Wayne Anderson, Sreekumar Pillai, Stephen RennardEmiel Wouters, Jørgen Vestbo, Alan Barker, Mark Brantly, Edward J. Campbell, Edward Eden, N. Gerard McElvaney, Robert Sandhaus, James Stocks, James Stoller, Charlie Strange, Gerard Turino

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Background: The identification of gene-by-environment interactions is important for understanding the genetic basis of chronic obstructive pulmonary disease (COPD). Many COPD genetic association analyses assume a linear relationship between pack-years of smoking exposure and forced expiratory volume in 1 s (FEV1); however, this assumption has not been evaluated empirically in cohorts with a wide spectrum of COPD severity. Methods: The relationship between FEV1and pack-years of smoking exposure was examined in four large cohorts assembled for the purpose of identifying genetic associations with COPD. Using data from the Alpha-1 Antitrypsin Genetic Modifiers Study, the accuracy and power of two different approaches to model smoking were compared by performing a simulation study of a genetic variant with a range of gene-by-smoking interaction effects. Results: Non-linear relationships between smoking and FEV1were identified in the four cohorts. It was found that, in most situations where the relationship between pack-years and FEV1is non-linear, a piecewise linear approach to model smoking and gene-by-smoking interactions is preferable to the commonly used total pack-years approach. The piecewise linear approach was applied to a genetic association analysis of the PI*Z allele in the Norway Case - Control cohort and a potential PI*Z-by-smoking interaction was identified (p=0.03 for FEV1analysis, p=0.01 for COPD susceptibility analysis). Conclusion: In study samples of subjects with a wide range of COPD severity, a non-linear relationship between pack-years of smoking and FEV1is likely. In this setting, approaches that account for this non-linearity can be more powerful and less biased than the more common approach of using total pack-years to model the smoking effect.

Original languageEnglish (US)
Pages (from-to)903-909
Number of pages7
JournalThorax
Volume66
Issue number10
DOIs
StatePublished - Oct 1 2011

Fingerprint

Chronic Obstructive Pulmonary Disease
Smoking
Genes
Gene-Environment Interaction
alpha 1-Antitrypsin
Disease Susceptibility
Forced Expiratory Volume
Norway
Alleles

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

Castaldi, P. J., Demeo, D. L., Hersh, C. P., Lomas, D. A., Soerheim, I. C., Gulsvik, A., ... Turino, G. (2011). Impact of non-linear smoking effects on the identification of gene-by-smoking interactions in COPD genetics studies. Thorax, 66(10), 903-909. https://doi.org/10.1136/thx.2010.146118

Impact of non-linear smoking effects on the identification of gene-by-smoking interactions in COPD genetics studies. / Castaldi, Peter J.; Demeo, D. L.; Hersh, C. P.; Lomas, D. A.; Soerheim, I. C.; Gulsvik, A.; Bakke, P.; Rennard, S.; Pare, Peter; Vestbo, J.; Silverman, E. K.; Agusti, Alvar; Calverley, Peter; Donner, Claudio F.; Levy, Robert D.; Lomas, David; Make, Barry J.; Anderson, Wayne; Pillai, Sreekumar; Rennard, Stephen; Wouters, Emiel; Vestbo, Jørgen; Barker, Alan; Brantly, Mark; Campbell, Edward J.; Eden, Edward; McElvaney, N. Gerard; Sandhaus, Robert; Stocks, James; Stoller, James; Strange, Charlie; Turino, Gerard.

In: Thorax, Vol. 66, No. 10, 01.10.2011, p. 903-909.

Research output: Contribution to journalArticle

Castaldi, PJ, Demeo, DL, Hersh, CP, Lomas, DA, Soerheim, IC, Gulsvik, A, Bakke, P, Rennard, S, Pare, P, Vestbo, J, Silverman, EK, Agusti, A, Calverley, P, Donner, CF, Levy, RD, Lomas, D, Make, BJ, Anderson, W, Pillai, S, Rennard, S, Wouters, E, Vestbo, J, Barker, A, Brantly, M, Campbell, EJ, Eden, E, McElvaney, NG, Sandhaus, R, Stocks, J, Stoller, J, Strange, C & Turino, G 2011, 'Impact of non-linear smoking effects on the identification of gene-by-smoking interactions in COPD genetics studies', Thorax, vol. 66, no. 10, pp. 903-909. https://doi.org/10.1136/thx.2010.146118
Castaldi, Peter J. ; Demeo, D. L. ; Hersh, C. P. ; Lomas, D. A. ; Soerheim, I. C. ; Gulsvik, A. ; Bakke, P. ; Rennard, S. ; Pare, Peter ; Vestbo, J. ; Silverman, E. K. ; Agusti, Alvar ; Calverley, Peter ; Donner, Claudio F. ; Levy, Robert D. ; Lomas, David ; Make, Barry J. ; Anderson, Wayne ; Pillai, Sreekumar ; Rennard, Stephen ; Wouters, Emiel ; Vestbo, Jørgen ; Barker, Alan ; Brantly, Mark ; Campbell, Edward J. ; Eden, Edward ; McElvaney, N. Gerard ; Sandhaus, Robert ; Stocks, James ; Stoller, James ; Strange, Charlie ; Turino, Gerard. / Impact of non-linear smoking effects on the identification of gene-by-smoking interactions in COPD genetics studies. In: Thorax. 2011 ; Vol. 66, No. 10. pp. 903-909.
@article{21fdbff551f8413495f2da30ab5a2a75,
title = "Impact of non-linear smoking effects on the identification of gene-by-smoking interactions in COPD genetics studies",
abstract = "Background: The identification of gene-by-environment interactions is important for understanding the genetic basis of chronic obstructive pulmonary disease (COPD). Many COPD genetic association analyses assume a linear relationship between pack-years of smoking exposure and forced expiratory volume in 1 s (FEV1); however, this assumption has not been evaluated empirically in cohorts with a wide spectrum of COPD severity. Methods: The relationship between FEV1and pack-years of smoking exposure was examined in four large cohorts assembled for the purpose of identifying genetic associations with COPD. Using data from the Alpha-1 Antitrypsin Genetic Modifiers Study, the accuracy and power of two different approaches to model smoking were compared by performing a simulation study of a genetic variant with a range of gene-by-smoking interaction effects. Results: Non-linear relationships between smoking and FEV1were identified in the four cohorts. It was found that, in most situations where the relationship between pack-years and FEV1is non-linear, a piecewise linear approach to model smoking and gene-by-smoking interactions is preferable to the commonly used total pack-years approach. The piecewise linear approach was applied to a genetic association analysis of the PI*Z allele in the Norway Case - Control cohort and a potential PI*Z-by-smoking interaction was identified (p=0.03 for FEV1analysis, p=0.01 for COPD susceptibility analysis). Conclusion: In study samples of subjects with a wide range of COPD severity, a non-linear relationship between pack-years of smoking and FEV1is likely. In this setting, approaches that account for this non-linearity can be more powerful and less biased than the more common approach of using total pack-years to model the smoking effect.",
author = "Castaldi, {Peter J.} and Demeo, {D. L.} and Hersh, {C. P.} and Lomas, {D. A.} and Soerheim, {I. C.} and A. Gulsvik and P. Bakke and S. Rennard and Peter Pare and J. Vestbo and Silverman, {E. K.} and Alvar Agusti and Peter Calverley and Donner, {Claudio F.} and Levy, {Robert D.} and David Lomas and Make, {Barry J.} and Wayne Anderson and Sreekumar Pillai and Stephen Rennard and Emiel Wouters and J{\o}rgen Vestbo and Alan Barker and Mark Brantly and Campbell, {Edward J.} and Edward Eden and McElvaney, {N. Gerard} and Robert Sandhaus and James Stocks and James Stoller and Charlie Strange and Gerard Turino",
year = "2011",
month = "10",
day = "1",
doi = "10.1136/thx.2010.146118",
language = "English (US)",
volume = "66",
pages = "903--909",
journal = "Thorax",
issn = "0040-6376",
publisher = "BMJ Publishing Group",
number = "10",

}

TY - JOUR

T1 - Impact of non-linear smoking effects on the identification of gene-by-smoking interactions in COPD genetics studies

AU - Castaldi, Peter J.

AU - Demeo, D. L.

AU - Hersh, C. P.

AU - Lomas, D. A.

AU - Soerheim, I. C.

AU - Gulsvik, A.

AU - Bakke, P.

AU - Rennard, S.

AU - Pare, Peter

AU - Vestbo, J.

AU - Silverman, E. K.

AU - Agusti, Alvar

AU - Calverley, Peter

AU - Donner, Claudio F.

AU - Levy, Robert D.

AU - Lomas, David

AU - Make, Barry J.

AU - Anderson, Wayne

AU - Pillai, Sreekumar

AU - Rennard, Stephen

AU - Wouters, Emiel

AU - Vestbo, Jørgen

AU - Barker, Alan

AU - Brantly, Mark

AU - Campbell, Edward J.

AU - Eden, Edward

AU - McElvaney, N. Gerard

AU - Sandhaus, Robert

AU - Stocks, James

AU - Stoller, James

AU - Strange, Charlie

AU - Turino, Gerard

PY - 2011/10/1

Y1 - 2011/10/1

N2 - Background: The identification of gene-by-environment interactions is important for understanding the genetic basis of chronic obstructive pulmonary disease (COPD). Many COPD genetic association analyses assume a linear relationship between pack-years of smoking exposure and forced expiratory volume in 1 s (FEV1); however, this assumption has not been evaluated empirically in cohorts with a wide spectrum of COPD severity. Methods: The relationship between FEV1and pack-years of smoking exposure was examined in four large cohorts assembled for the purpose of identifying genetic associations with COPD. Using data from the Alpha-1 Antitrypsin Genetic Modifiers Study, the accuracy and power of two different approaches to model smoking were compared by performing a simulation study of a genetic variant with a range of gene-by-smoking interaction effects. Results: Non-linear relationships between smoking and FEV1were identified in the four cohorts. It was found that, in most situations where the relationship between pack-years and FEV1is non-linear, a piecewise linear approach to model smoking and gene-by-smoking interactions is preferable to the commonly used total pack-years approach. The piecewise linear approach was applied to a genetic association analysis of the PI*Z allele in the Norway Case - Control cohort and a potential PI*Z-by-smoking interaction was identified (p=0.03 for FEV1analysis, p=0.01 for COPD susceptibility analysis). Conclusion: In study samples of subjects with a wide range of COPD severity, a non-linear relationship between pack-years of smoking and FEV1is likely. In this setting, approaches that account for this non-linearity can be more powerful and less biased than the more common approach of using total pack-years to model the smoking effect.

AB - Background: The identification of gene-by-environment interactions is important for understanding the genetic basis of chronic obstructive pulmonary disease (COPD). Many COPD genetic association analyses assume a linear relationship between pack-years of smoking exposure and forced expiratory volume in 1 s (FEV1); however, this assumption has not been evaluated empirically in cohorts with a wide spectrum of COPD severity. Methods: The relationship between FEV1and pack-years of smoking exposure was examined in four large cohorts assembled for the purpose of identifying genetic associations with COPD. Using data from the Alpha-1 Antitrypsin Genetic Modifiers Study, the accuracy and power of two different approaches to model smoking were compared by performing a simulation study of a genetic variant with a range of gene-by-smoking interaction effects. Results: Non-linear relationships between smoking and FEV1were identified in the four cohorts. It was found that, in most situations where the relationship between pack-years and FEV1is non-linear, a piecewise linear approach to model smoking and gene-by-smoking interactions is preferable to the commonly used total pack-years approach. The piecewise linear approach was applied to a genetic association analysis of the PI*Z allele in the Norway Case - Control cohort and a potential PI*Z-by-smoking interaction was identified (p=0.03 for FEV1analysis, p=0.01 for COPD susceptibility analysis). Conclusion: In study samples of subjects with a wide range of COPD severity, a non-linear relationship between pack-years of smoking and FEV1is likely. In this setting, approaches that account for this non-linearity can be more powerful and less biased than the more common approach of using total pack-years to model the smoking effect.

UR - http://www.scopus.com/inward/record.url?scp=80053221997&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80053221997&partnerID=8YFLogxK

U2 - 10.1136/thx.2010.146118

DO - 10.1136/thx.2010.146118

M3 - Article

C2 - 21163806

AN - SCOPUS:80053221997

VL - 66

SP - 903

EP - 909

JO - Thorax

JF - Thorax

SN - 0040-6376

IS - 10

ER -