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

Hugues Aschard^{1

2}, Martin D Tobin^{3

4}, Dana B Hancock⁵, David Skurnik⁶, Akshay Sood⁷, Alan James^{8

9}, Albert Vernon Smith^{10

11}, Ani W Manichaikul^{12

13}, Archie Campbell^{14

15}, Bram P Prins¹⁶, Caroline Hayward¹⁷, Daan W Loth¹⁸, David J Porteous^{14

15}, David P Strachan¹⁹, Eleftheria Zeggini¹⁶, George T O'Connor^{20

21}, Guy G Brusselle^{18

22

23}, H Marike Boezen^{24

25}, Holger Schulz^{26

27}, Ian J Deary^{28

29}, Ian P Hall³⁰, Igor Rudan³¹, Jaakko Kaprio^{32

33

34}, James F Wilson^{17

31}, Jemma B Wilk²⁰, Jennifer E Huffman¹⁷, Jing Hua Zhao^{35

36}, Kim de Jong^{24

25}, Leo-Pekka Lyytikäinen^{37

38}, Louise V Wain^{3

4}, Marjo-Riitta Jarvelin^{39

40

41

42}, Mika Kähönen⁴³, Myriam Fornage⁴⁴, Ozren Polasek^{31

45}, Patricia A Cassano^{46

47}, R Graham Barr⁴⁸, Rajesh Rawal^{49

50

51}, Sarah E Harris^{14

28}, Sina A Gharib^{52

53}, Stefan Enroth⁵⁴, Susan R Heckbert⁵⁵, Terho Lehtimäki^{37

38}, Ulf Gyllensten⁵⁴; Understanding Society Scientific Group; Victoria E Jackson³, Vilmundur Gudnason^{10

11}, Wenbo Tang^{46

55}, Josée Dupuis^{20

56}, María Soler Artigas³, Amit D Joshi^{1

2

57}, Stephanie J London⁵⁸, Peter Kraft^{1

2}

Affiliations

¹ Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, USA.
² Program in Genetic Epidemiology and Statistical Genetics, Harvard TH Chan School of Public Health, Boston, MA, USA.
³ Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester, UK.
⁴ National Institute for Health Research, Leicester Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
⁵ Behavioral and Urban Health Program, Behavioral Health and Criminal Justice Research Division, Research Triangle Institute (RTI) International, Research Triangle Park, NC, USA.
⁶ Division of Infectious Diseases, Brigham and Women Hospital, Harvard Medical School, Boston, MA, USA.
⁷ Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM, USA.
⁸ Department of Pulmonary Physiology and Sleep Medicine, Sir Charles Gairdner Hospital, Nedlands, Australia.
⁹ School of Medicine and Pharmacology, University of Western Australia, Crawley, Australia.
¹⁰ Icelandic Heart Association, Kopavogur, Iceland.
¹¹ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
¹² Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
¹³ Department of Public Health Sciences, Division of Biostatistics and Epidemiology, University of Virginia, Charlottesville, VA, USA.
¹⁴ Centre for Genomic & Experimental Medicine, Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, UK.
¹⁵ Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, UK.
¹⁶ Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, UK.
¹⁷ MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
¹⁸ Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
¹⁹ Population Health Research Institute, St George's University of London, London, UK.
²⁰ The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA.
²¹ The Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
²² Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
²³ Department of Respiratory Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
²⁴ University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, The Netherlands.
²⁵ University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Groningen, The Netherlands.
²⁶ Institute of Epidemiology I, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
²⁷ Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research, Munich, Germany.
²⁸ Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
²⁹ Department of Psychology, University of Edinburgh, Edinburgh, UK.
³⁰ Division of Respiratory Medicine, University of Nottingham, Queen's Medical Centre, Nottingham, UK.
³¹ Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
³² Department of Public Health, University of Helsinki, Helsinki, Finland.
³³ Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland.
³⁴ National Institute for Health and Welfare, Department of Health, Helsinki, Finland.
³⁵ MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK.
³⁶ Institute of Metabolic Science, Biomedical Campus, Cambridge, UK.
³⁷ Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland.
³⁸ Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, Finland.
³⁹ Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment & Health, School of Public Health, Imperial College London, UK.
⁴⁰ Center for Life Course Epidemiology, Faculty of Medicine, University of Oulu, Oulu, Finland.
⁴¹ Biocenter Oulu, University of Oulu, Oulu, Finland.
⁴² Unit of Primary Care, Oulu University Hospital, Oulu, Finland.
⁴³ Department of Clinical Physiology, University of Tampere and Tampere University Hospital, Tampere, Finland.
⁴⁴ Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.
⁴⁵ Faculty of Medicine, University of Split, Split, Croatia.
⁴⁶ Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA.
⁴⁷ Department of Healthcare Policy and Research, Weill Cornell Medical College, NY, NY, USA.
⁴⁸ Departments of Medicine and Epidemiology, Columbia University Medical Center.
⁴⁹ Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
⁵⁰ Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
⁵¹ Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
⁵² Computational Medicine Core at Center for Lung Biology, Division of Pulmonary & Critical Care Medicine, University of Washington, Seattle, WA.
⁵³ Cardiovascular Health Research Unit and Department of Epidemiology, University of Washington, Seattle, WA, USA.
⁵⁴ Department of Immunology, Genetics and Pathology, Uppsala Universitet, Science for Life Laboratory, Uppsala, Sweden.
⁵⁵ Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA.
⁵⁶ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
⁵⁷ Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA. Human Services, Research Triangle Park, NC, USA.
⁵⁸ Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, US Department of Health and Human Services, Research Triangle Park, NC, USA.

PMID: 28082375
PMCID: PMC5837518
DOI: 10.1093/ije/dyw318

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

Hugues Aschard et al. Int J Epidemiol. 2017.

. 2017 Jun 1;46(3):894-904.

doi: 10.1093/ije/dyw318.

Authors

Affiliations

¹ Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, USA.
² Program in Genetic Epidemiology and Statistical Genetics, Harvard TH Chan School of Public Health, Boston, MA, USA.
³ Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester, UK.
⁴ National Institute for Health Research, Leicester Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
⁵ Behavioral and Urban Health Program, Behavioral Health and Criminal Justice Research Division, Research Triangle Institute (RTI) International, Research Triangle Park, NC, USA.
⁶ Division of Infectious Diseases, Brigham and Women Hospital, Harvard Medical School, Boston, MA, USA.
⁷ Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM, USA.
⁸ Department of Pulmonary Physiology and Sleep Medicine, Sir Charles Gairdner Hospital, Nedlands, Australia.
⁹ School of Medicine and Pharmacology, University of Western Australia, Crawley, Australia.
¹⁰ Icelandic Heart Association, Kopavogur, Iceland.
¹¹ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
¹² Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
¹³ Department of Public Health Sciences, Division of Biostatistics and Epidemiology, University of Virginia, Charlottesville, VA, USA.
¹⁴ Centre for Genomic & Experimental Medicine, Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, UK.
¹⁵ Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, UK.
¹⁶ Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, UK.
¹⁷ MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
¹⁸ Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
¹⁹ Population Health Research Institute, St George's University of London, London, UK.
²⁰ The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA.
²¹ The Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
²² Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
²³ Department of Respiratory Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
²⁴ University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, The Netherlands.
²⁵ University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Groningen, The Netherlands.
²⁶ Institute of Epidemiology I, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
²⁷ Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research, Munich, Germany.
²⁸ Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
²⁹ Department of Psychology, University of Edinburgh, Edinburgh, UK.
³⁰ Division of Respiratory Medicine, University of Nottingham, Queen's Medical Centre, Nottingham, UK.
³¹ Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
³² Department of Public Health, University of Helsinki, Helsinki, Finland.
³³ Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland.
³⁴ National Institute for Health and Welfare, Department of Health, Helsinki, Finland.
³⁵ MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK.
³⁶ Institute of Metabolic Science, Biomedical Campus, Cambridge, UK.
³⁷ Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland.
³⁸ Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, Finland.
³⁹ Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment & Health, School of Public Health, Imperial College London, UK.
⁴⁰ Center for Life Course Epidemiology, Faculty of Medicine, University of Oulu, Oulu, Finland.
⁴¹ Biocenter Oulu, University of Oulu, Oulu, Finland.
⁴² Unit of Primary Care, Oulu University Hospital, Oulu, Finland.
⁴³ Department of Clinical Physiology, University of Tampere and Tampere University Hospital, Tampere, Finland.
⁴⁴ Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.
⁴⁵ Faculty of Medicine, University of Split, Split, Croatia.
⁴⁶ Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA.
⁴⁷ Department of Healthcare Policy and Research, Weill Cornell Medical College, NY, NY, USA.
⁴⁸ Departments of Medicine and Epidemiology, Columbia University Medical Center.
⁴⁹ Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
⁵⁰ Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
⁵¹ Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
⁵² Computational Medicine Core at Center for Lung Biology, Division of Pulmonary & Critical Care Medicine, University of Washington, Seattle, WA.
⁵³ Cardiovascular Health Research Unit and Department of Epidemiology, University of Washington, Seattle, WA, USA.
⁵⁴ Department of Immunology, Genetics and Pathology, Uppsala Universitet, Science for Life Laboratory, Uppsala, Sweden.
⁵⁵ Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA.
⁵⁶ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
⁵⁷ Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA. Human Services, Research Triangle Park, NC, USA.
⁵⁸ Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, US Department of Health and Human Services, Research Triangle Park, NC, USA.

PMID: 28082375
PMCID: PMC5837518
DOI: 10.1093/ije/dyw318

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 FEV 1 (forced expiratory volume in 1 second) or FEV 1 /FVC (FEV 1 /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 FEV 1 or FEV 1 /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 FEV 1 /FVC ratio. In interpreting this interaction, we showed that the genetic risk of falling below the FEV /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 FEV 1 /FVC may be more susceptible to the deleterious effects of smoking.

Keywords: FEV1/FVC; genetic risk score; gene–environment interaction; smoking.

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Figures

**Figure 1.**
Distribution of interaction effects on FEV₁/FVC. Single SNP risk allele-by-smoking status (ever/never) interaction effect estimates (*β_int*) and 95% confidence intervals are plotted by increasing values. The unweighted genetic risk score-by-smoking status interaction is plotted at the bottom.

**Figure 2.**
Overview of the unweighted genetic risk score-by-smoking interaction effect on FEV₁/FVC. Upper panel (A) presents the distribution of the unweighted genetic risk score (GRS, grey density plot) and the relationship between the unweighted GRS and standardized FEV₁/FVC in ever smokers (dashed line) and never smokers (solid line). Lower panel (B) shows the excess relative risk (RR) of having FEV₁/FVC in the lowest 1%, 5% and 20% of the population for ever smokers compared with never smokers, as stratified by GRS quintiles.

**Figure 3.**
Underlying causal model. Potential causal diagrams underlying the gene and smoking interaction effects on FEV₁/FVC. Panel (A) presents a scenario where each genetic variant influences the outcome through a SNP-specific pathway, and interactions with the environmental exposure take place along these pathways. Panel (B) presents an alternative (and simpler) model where multiple genetic variants influence an unmeasured intermediate biomarker U, which effect on FEV₁/FVC depends on smoking. In scenario (A), the single SNP-by-smoking interaction test is the optimal approach, whereas, in scenario (B), the single SNP-by-smoking interaction test can become inefficient, and interaction would be easier to detect using a genetic risk score-by-smoking interaction test, because it summarizes all interaction effects in a single test.

See this image and copyright information in PMC

References

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

Affiliations

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

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources