Evidence for large-scale gene-by-smoking interaction effects on pulmonary function

Hugues Aschard; Martin D Tobin; Dana B. Hancock; David Skurnik; Akshay Sood; Alan James; Albert Vernon Smith; Ani Manichaikul; Archie Campbell; Bram P Prins; Caroline Hayward; Daan W. Loth; David Porteous; David P Strachan; Eleftheria Zeggini; George T. O'Connor; Guy G. Brusselle; H. Marike Boezen; Holger Schulz; Ian J Deary; Ian P Hall; Igor Rudan; Jaakko Kaprio; James Wilson; Jemma B. Wilk; Jennifer Huffman; Jing Hua Zhao; Kim de Jong; Leo-Pekka Lyytikäinen; Louise V Wain; Marjo-Riitta Jarvelin; Mika Kahonen; Myriam Fornage; Ozren Polasek; Patricia A. Cassano; R. Graham Barr; Rajesh Rawal; Sarah Harris; Sina A. Gharib; Stefan Enroth; Susan R. Heckbert; Terho Lehtimaki; Ulf Gyllensten; Victoria E Jackson; Vilmundur Gudnason; Wenbo Tang; Josee Dupuis; María Soler Artigas; Amit D Joshi; Peter Kraft

doi:10.1093/ije/dyw318

Evidence for large-scale gene-by-smoking interaction effects on pulmonary function

Hugues Aschard, Martin D Tobin, Dana B. Hancock, David Skurnik, Akshay Sood, Alan James, Albert Vernon Smith, Ani Manichaikul, Archie Campbell, Bram P Prins, Caroline Hayward, Daan W. Loth, David Porteous, David P Strachan, Eleftheria Zeggini, George T. O'Connor, Guy G. Brusselle, H. Marike Boezen, Holger Schulz, Ian J DearyIan P Hall, Igor Rudan, Jaakko Kaprio, James Wilson, Jemma B. Wilk, Jennifer Huffman, Jing Hua Zhao, Kim de Jong, Leo-Pekka Lyytikäinen, Louise V Wain, Marjo-Riitta Jarvelin, Mika Kahonen, Myriam Fornage, Ozren Polasek, Patricia A. Cassano, R. Graham Barr, Rajesh Rawal, Sarah Harris, Sina A. Gharib, Stefan Enroth, Susan R. Heckbert, Terho Lehtimaki, Ulf Gyllensten, Victoria E Jackson, Vilmundur Gudnason, Wenbo Tang, Josee Dupuis, María Soler Artigas, Amit D Joshi, Peter Kraft

Research output: Contribution to journal › Article › peer-review

Abstract

Background: Smoking is the strongest environmental risk factor for reduced pulmonary function. The genetic component of various pulmonary traits has also been demonstrated, and at least 26 loci have been reproducibly associated with either FEV1 (forced expiratory volume in 1 second) or FEV1/FVC (FEV1/forced vital capacity). Although the main effects of smoking and genetic loci are well established, the question of potential gene-by-smoking interaction effect remains unanswered. The aim of the present study was to assess, using a genetic risk score approach, whether the effect of these 26 loci on pulmonary function is influenced by smoking.

Methods: We evaluated the interaction between smoking exposure, considered as either ever vs never or pack-years, and a 26-single nucleotide polymorphisms (SNPs) genetic risk score in relation to FEV1 or FEV1/FVC in 50 047 participants of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) and SpiroMeta consortia.

Results: We identified an interaction (βint = –0.036, 95% confidence interval, –0.040 to –0.032, P = 0.00057) between an unweighted 26 SNP genetic risk score and smoking status (ever/never) on the FEV1/FVC ratio. In interpreting this interaction, we showed that the genetic risk of falling below the FEV1/FVC threshold used to diagnose chronic obstructive pulmonary disease is higher among ever smokers than among never smokers. A replication analysis in two independent datasets, although not statistically significant, showed a similar trend in the interaction effect.

Conclusions: This study highlights the benefit of using genetic risk scores for identifying interactions missed when studying individual SNPs and shows, for the first time, that persons with the highest genetic risk for low FEV1/FVC may be more susceptible to the deleterious effects of smoking.

Original language	English
Journal	International Journal of Epidemiology
Early online date	12 Jan 2017
DOIs	https://doi.org/10.1093/ije/dyw318
Publication status	E-pub ahead of print - 12 Jan 2017

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10.1093/ije/dyw318

Int. J. Epidemiol.-2017-Aschard-ije-dyw318Final published version, 636 KB

RA2661 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2. Main Budget.
Deary, I. (Principal Investigator), Gale, C. (Co-investigator), Holmes, M. (Co-investigator), Logie, P. (Co-investigator), Maclullich, A. (Co-investigator), Porteous, D. (Co-investigator), Seckl, J. (Co-investigator), Starr, J. (Co-investigator), Wardlaw, J. (Co-investigator) & Okely, J. (Researcher)
1/09/13 → 31/08/19
Project: Research

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Aschard, H., Tobin, M. D., Hancock, D. B., Skurnik, D., Sood, A., James, A., Smith, A. V., Manichaikul, A., Campbell, A., Prins, B. P., Hayward, C., Loth, D. W., Porteous, D., Strachan, D. P., Zeggini, E., O'Connor, G. T., Brusselle, G. G., Boezen, H. M., Schulz, H., ... Kraft, P. (2017). Evidence for large-scale gene-by-smoking interaction effects on pulmonary function. International Journal of Epidemiology. Advance online publication. https://doi.org/10.1093/ije/dyw318

@article{d4cb0dde2df145cb92849b29a4fafd87,

title = "Evidence for large-scale gene-by-smoking interaction effects on pulmonary function",

abstract = "Background: Smoking is the strongest environmental risk factor for reduced pulmonary function. The genetic component of various pulmonary traits has also been demonstrated, and at least 26 loci have been reproducibly associated with either FEV1 (forced expiratory volume in 1 second) or FEV1/FVC (FEV1/forced vital capacity). Although the main effects of smoking and genetic loci are well established, the question of potential gene-by-smoking interaction effect remains unanswered. The aim of the present study was to assess, using a genetic risk score approach, whether the effect of these 26 loci on pulmonary function is influenced by smoking.Methods: We evaluated the interaction between smoking exposure, considered as either ever vs never or pack-years, and a 26-single nucleotide polymorphisms (SNPs) genetic risk score in relation to FEV1 or FEV1/FVC in 50 047 participants of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) and SpiroMeta consortia.Results: We identified an interaction (βint = –0.036, 95% confidence interval, –0.040 to –0.032, P = 0.00057) between an unweighted 26 SNP genetic risk score and smoking status (ever/never) on the FEV1/FVC ratio. In interpreting this interaction, we showed that the genetic risk of falling below the FEV1/FVC threshold used to diagnose chronic obstructive pulmonary disease is higher among ever smokers than among never smokers. A replication analysis in two independent datasets, although not statistically significant, showed a similar trend in the interaction effect.Conclusions: This study highlights the benefit of using genetic risk scores for identifying interactions missed when studying individual SNPs and shows, for the first time, that persons with the highest genetic risk for low FEV1/FVC may be more susceptible to the deleterious effects of smoking.",

author = "Hugues Aschard and Tobin, {Martin D} and Hancock, {Dana B.} and David Skurnik and Akshay Sood and Alan James and Smith, {Albert Vernon} and Ani Manichaikul and Archie Campbell and Prins, {Bram P} and Caroline Hayward and Loth, {Daan W.} and David Porteous and Strachan, {David P} and Eleftheria Zeggini and O'Connor, {George T.} and Brusselle, {Guy G.} and Boezen, {H. Marike} and Holger Schulz and Deary, {Ian J} and Hall, {Ian P} and Igor Rudan and Jaakko Kaprio and James Wilson and Wilk, {Jemma B.} and Jennifer Huffman and Zhao, {Jing Hua} and {de Jong}, Kim and Leo-Pekka Lyytik{\"a}inen and Wain, {Louise V} and Marjo-Riitta Jarvelin and Mika Kahonen and Myriam Fornage and Ozren Polasek and Cassano, {Patricia A.} and Barr, {R. Graham} and Rajesh Rawal and Sarah Harris and Gharib, {Sina A.} and Stefan Enroth and Heckbert, {Susan R.} and Terho Lehtimaki and Ulf Gyllensten and Jackson, {Victoria E} and Vilmundur Gudnason and Wenbo Tang and Josee Dupuis and Artigas, {Mar{\'i}a Soler} and Joshi, {Amit D} and Peter Kraft",

year = "2017",

month = jan,

day = "12",

doi = "10.1093/ije/dyw318",

language = "English",

journal = "International Journal of Epidemiology",

issn = "0300-5771",

publisher = "Oxford University Press",

}

Aschard, H, Tobin, MD, Hancock, DB, Skurnik, D, Sood, A, James, A, Smith, AV, Manichaikul, A, Campbell, A, Prins, BP, Hayward, C, Loth, DW, Porteous, D, Strachan, DP, Zeggini, E, O'Connor, GT, Brusselle, GG, Boezen, HM, Schulz, H, Deary, IJ, Hall, IP, Rudan, I, Kaprio, J, Wilson, J, Wilk, JB, Huffman, J, Zhao, JH, de Jong, K, Lyytikäinen, L-P, Wain, LV, Jarvelin, M-R, Kahonen, M, Fornage, M, Polasek, O, Cassano, PA, Barr, RG, Rawal, R, Harris, S, Gharib, SA, Enroth, S, Heckbert, SR, Lehtimaki, T, Gyllensten, U, Jackson, VE, Gudnason, V, Tang, W, Dupuis, J, Artigas, MS, Joshi, AD & Kraft, P 2017, 'Evidence for large-scale gene-by-smoking interaction effects on pulmonary function', International Journal of Epidemiology. https://doi.org/10.1093/ije/dyw318

TY - JOUR

T1 - Evidence for large-scale gene-by-smoking interaction effects on pulmonary function

AU - Aschard, Hugues

AU - Tobin, Martin D

AU - Hancock, Dana B.

AU - Skurnik, David

AU - Sood, Akshay

AU - James, Alan

AU - Smith, Albert Vernon

AU - Manichaikul, Ani

AU - Campbell, Archie

AU - Prins, Bram P

AU - Hayward, Caroline

AU - Loth, Daan W.

AU - Porteous, David

AU - Strachan, David P

AU - Zeggini, Eleftheria

AU - O'Connor, George T.

AU - Brusselle, Guy G.

AU - Boezen, H. Marike

AU - Schulz, Holger

AU - Deary, Ian J

AU - Hall, Ian P

AU - Rudan, Igor

AU - Kaprio, Jaakko

AU - Wilson, James

AU - Wilk, Jemma B.

AU - Huffman, Jennifer

AU - Zhao, Jing Hua

AU - de Jong, Kim

AU - Lyytikäinen, Leo-Pekka

AU - Wain, Louise V

AU - Jarvelin, Marjo-Riitta

AU - Kahonen, Mika

AU - Fornage, Myriam

AU - Polasek, Ozren

AU - Cassano, Patricia A.

AU - Barr, R. Graham

AU - Rawal, Rajesh

AU - Harris, Sarah

AU - Gharib, Sina A.

AU - Enroth, Stefan

AU - Heckbert, Susan R.

AU - Lehtimaki, Terho

AU - Gyllensten, Ulf

AU - Jackson, Victoria E

AU - Gudnason, Vilmundur

AU - Tang, Wenbo

AU - Dupuis, Josee

AU - Artigas, María Soler

AU - Joshi, Amit D

AU - Kraft, Peter

PY - 2017/1/12

Y1 - 2017/1/12

N2 - Background: Smoking is the strongest environmental risk factor for reduced pulmonary function. The genetic component of various pulmonary traits has also been demonstrated, and at least 26 loci have been reproducibly associated with either FEV1 (forced expiratory volume in 1 second) or FEV1/FVC (FEV1/forced vital capacity). Although the main effects of smoking and genetic loci are well established, the question of potential gene-by-smoking interaction effect remains unanswered. The aim of the present study was to assess, using a genetic risk score approach, whether the effect of these 26 loci on pulmonary function is influenced by smoking.Methods: We evaluated the interaction between smoking exposure, considered as either ever vs never or pack-years, and a 26-single nucleotide polymorphisms (SNPs) genetic risk score in relation to FEV1 or FEV1/FVC in 50 047 participants of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) and SpiroMeta consortia.Results: We identified an interaction (βint = –0.036, 95% confidence interval, –0.040 to –0.032, P = 0.00057) between an unweighted 26 SNP genetic risk score and smoking status (ever/never) on the FEV1/FVC ratio. In interpreting this interaction, we showed that the genetic risk of falling below the FEV1/FVC threshold used to diagnose chronic obstructive pulmonary disease is higher among ever smokers than among never smokers. A replication analysis in two independent datasets, although not statistically significant, showed a similar trend in the interaction effect.Conclusions: This study highlights the benefit of using genetic risk scores for identifying interactions missed when studying individual SNPs and shows, for the first time, that persons with the highest genetic risk for low FEV1/FVC may be more susceptible to the deleterious effects of smoking.

AB - Background: Smoking is the strongest environmental risk factor for reduced pulmonary function. The genetic component of various pulmonary traits has also been demonstrated, and at least 26 loci have been reproducibly associated with either FEV1 (forced expiratory volume in 1 second) or FEV1/FVC (FEV1/forced vital capacity). Although the main effects of smoking and genetic loci are well established, the question of potential gene-by-smoking interaction effect remains unanswered. The aim of the present study was to assess, using a genetic risk score approach, whether the effect of these 26 loci on pulmonary function is influenced by smoking.Methods: We evaluated the interaction between smoking exposure, considered as either ever vs never or pack-years, and a 26-single nucleotide polymorphisms (SNPs) genetic risk score in relation to FEV1 or FEV1/FVC in 50 047 participants of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) and SpiroMeta consortia.Results: We identified an interaction (βint = –0.036, 95% confidence interval, –0.040 to –0.032, P = 0.00057) between an unweighted 26 SNP genetic risk score and smoking status (ever/never) on the FEV1/FVC ratio. In interpreting this interaction, we showed that the genetic risk of falling below the FEV1/FVC threshold used to diagnose chronic obstructive pulmonary disease is higher among ever smokers than among never smokers. A replication analysis in two independent datasets, although not statistically significant, showed a similar trend in the interaction effect.Conclusions: This study highlights the benefit of using genetic risk scores for identifying interactions missed when studying individual SNPs and shows, for the first time, that persons with the highest genetic risk for low FEV1/FVC may be more susceptible to the deleterious effects of smoking.

U2 - 10.1093/ije/dyw318

DO - 10.1093/ije/dyw318

M3 - Article

SN - 0300-5771

JO - International Journal of Epidemiology

JF - International Journal of Epidemiology

ER -

Evidence for large-scale gene-by-smoking interaction effects on pulmonary function

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RA2661 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2. Main Budget.

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