University of Oulu

Hugues Aschard, Martin D Tobin, Dana B Hancock, David Skurnik, Akshay Sood, Alan James, Albert Vernon Smith, Ani W Manichaikul, Archie Campbell, Bram P Prins, Caroline Hayward, Daan W Loth, David J 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 F Wilson, Jemma B Wilk, Jennifer E Huffman, Jing Hua Zhao, Kim de Jong, Leo-Pekka Lyytikäinen, Louise V Wain, Marjo-Riitta Jarvelin, Mika Kähönen, Myriam Fornage, Ozren Polasek, Patricia A Cassano, R Graham Barr, Rajesh Rawal, Sarah E Harris, Sina A Gharib, Stefan Enroth, Susan R Heckbert, Terho Lehtimäki, Ulf Gyllensten, Understanding Society Scientific Group, Victoria E Jackson, Vilmundur Gudnason, Wenbo Tang, Josée Dupuis, María Soler Artigas, Amit D Joshi, Stephanie J London, Peter Kraft; Evidence for large-scale gene-by-smoking interaction effects on pulmonary function, International Journal of Epidemiology, Volume 46, Issue 3, 1 June 2017, Pages 894–904,

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

Saved in:
Author: Aschard, Hugues1,2; Tobin, Martin D3,4; Hancock, Dana B5;
Organizations: 1Department of Epidemiology, Harvard TH Chan School of Public Health
2Program in Genetic Epidemiology and Statistical Genetics, Harvard TH Chan School of Public Health
3Genetic Epidemiology Group, Department of Health Sciences, University of Leicester
4National Institute for Health Research, Leicester Respiratory Biomedical Research Unit, Glenfield Hospital
5Behavioral and Urban Health Program, Behavioral Health and Criminal Justice Research Division, Research Triangle Institute (RTI) International
6Division of Infectious Diseases, Brigham and Women Hospital, Harvard Medical School
7Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of New Mexico School of Medicine
8Department of Pulmonary Physiology and Sleep Medicine, Sir Charles Gairdner Hospital
9School of Medicine and Pharmacology, University of Western Australia
10Icelandic Heart Association
11Faculty of Medicine, University of Iceland
12Center for Public Health Genomics, University of Virginia
13Department of Public Health Sciences, Division of Biostatistics and Epidemiology
14Centre for Genomic & Experimental Medicine, Institute of Genetics & Molecular Medicine, University of Edinburgh
15Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh
16Department of Human Genetics, Wellcome Trust Sanger Institute
17MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh
18Department of Epidemiology, Erasmus Medical Center
19Population Health Research Institute, St George’s University of London
20The National Heart, Lung, and Blood Institute’s Framingham Heart Study
21The Pulmonary Center, Department of Medicine, Boston University School of Medicine
22Department of Respiratory Medicine, Ghent University Hospital
23Department of Respiratory Medicine, Erasmus Medical Center
24University of Groningen, University Medical Center Groningen, Department of Epidemiology
25University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD
26Institute of Epidemiology I, Helmholtz Zentrum Mu¨nchen, German Research Center for Environmental Health
27Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research
28Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh
29Department of Psychology, University of Edinburgh, Edinburgh
30Division of Respiratory Medicine, University of Nottingham, Queen’s Medical Centre
31Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh
32Department of Public Health, University of Helsinki
33Institute for Molecular Medicine, University of Helsinki
34National Institute for Health and Welfare, Department of Health
35MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine
36Institute of Metabolic Science, Biomedical Campus, Cambridge
37Department of Clinical Chemistry, Fimlab Laboratories
38Department of Clinical Chemistry, University of Tampere School of Medicine
39Department of Epidemiology and Biostatistics, MRC–PHE Centre for Environment & Health, School of Public Health, Imperial College London
40Center for Life Course Epidemiology, Faculty of Medicine, University of Oulu
41Biocenter Oulu, University of Oulu
42Unit of Primary Care, Oulu University Hospital
43Department of Clinical Physiology, University of Tampere and Tampere University Hospital
44Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston
45Faculty of Medicine, University of Split
46Division of Nutritional Sciences, Cornell University
47Department of Healthcare Policy and Research, Weill Cornell Medical College
48Departments of Medicine and Epidemiology, Columbia University Medical Center
49Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health
50Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health
51Computational Medicine Core at Center for Lung Biology, Division of Pulmonary & Critical Care Medicine, University of Washington
52Department of Immunology, Genetics and Pathology, Uppsala Universitet, Science for Life Laboratory, Uppsala
53Boehringer Ingelheim Pharmaceuticals, Inc.
54Department of Biostatistics, Boston University School of Public Health
55Division of Gastroenterology, Massachusetts General Hospital. Human Services
56Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, US Department of Health and Human Services
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 0.5 MB)
Persistent link:
Language: English
Published: Oxford University Press, 2017
Publish Date: 2017-08-28


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.

see all

Series: International journal of epidemiology
ISSN: 0300-5771
ISSN-E: 1464-3685
ISSN-L: 0300-5771
Volume: 46
Issue: 3
Pages: 894 - 904
DOI: 10.1093/ije/dyw318
Type of Publication: A1 Journal article – refereed
Field of Science: 3141 Health care science
3111 Biomedicine
Funding: Acknowledgments for all studies included in the prior meta-analyses, from which we derived results for the current study, were outlined in Hancock et al.4 or Soler Artigas et al.3 Acknowledgment for the cohorts with authors represented in the current study: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE): Infrastructure for the CHARGE Consortium is supported in part by the National Heart, Lung, and Blood Institute (NHLBI) grant R01HL105756. Atherosclerosis Risk in Communities Study (ARIC): ARIC is carried out as a collaborative study supported by NHLBI contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute (NHGRI) contract U01HG004402; and National Institutes of Health (NIH) contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by grant number UL1RR025005, a component of the NIH and NIH Roadmap for Medical Research. Cardiovascular Health Study (CHS): CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided through R01AG023629 from the National Institute on Aging. A full list of principal CHS investigators and institutions can be found at The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant L1TR000124, and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Diabetes Research Center grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Framingham Heart Study (FHS): FHS research was conducted in part using data and resources of the NHLBI and Boston University School of Medicine. This work was partially supported by NHLBI (contract no. N01-HC-25195 and HHSN268201500001I) and its contract with Affymetrix for genotyping services (contract no. N02-HL-6-4278). Multi-Ethnic Study of Atherosclerosis (MESA): The MESA Lung study and the MESA SHARe project are conducted and supported by NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-001079, UL1-TR-000040, and DK063491. The MESA Lung Study is funded by R01HL077612, RC1100543, and R01H093081. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, California, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0. British 1958 Birth Cohort (B58C): We acknowledge use of phenotype and genotype data from the B58C DNA collection, funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02. Genotyping for the B58C-WTCCC subset was funded by the Wellcome Trust grant 076113/B/04/Z. The B58C-T1DGC genotyping used resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the NIDDK, National Institute of Allergy and Infectious Diseases, NHGRI, National Institute of Child Health and Human Development, and Juvenile Diabetes Research Foundation International and supported by U01 DK062418. B58C-T1DGC GWAS data were deposited by the Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research (CIMR), University of Cambridge, which is funded by Juvenile Diabetes Research Foundation International, the Wellcome Trust, and the National Institute for Health Research Cambridge Biomedical Research Centre; the CIMR is in receipt of a Wellcome Trust Strategic Award (079895). The B58C-GABRIEL genotyping was supported by a contract from the European Commission Framework Programme 6 (018996) and grants from the French Ministry of Research. Northern Finland Birth Cohort 1966 (NFBC1966): NFBC1966 received financial support from the Academy of Finland (project grants 104781, 120315, 129269, 1114194, 24300796, Center of Excellence in Complex Disease Genetics and SALVE), University Hospital Oulu, Biocenter, University of Oulu, Finland (75617), NHLBI grant 5R01HL087679-02 through the STAMPEED program (1RL1MH083268-01), NIH/NIMH (5R01MH63706:02), ENGAGE project and grant agreement HEALTH-F4- 2007-201413, EU FP7 EurHEALTHAgeing -277849, the Medical Research Council, UK (G0500539, G0600705, G1002319, PrevMetSyn/SALVE) and the MRC, Centenary Early Career Award. The program is currently being funded by the H2020-633595 DynaHEALTH action and academy of Finland EGEA-project (285547). The DNA extractions, sample quality controls, biobank upkeep, and aliquotting was performed in the National Public Health Institute, Biomedicum Helsinki, Finland, and supported financially by the Academy of Finland and Biocentrum Helsinki. We thank the late Professor Paula Rantakallio (launch of NFBCs), and Ms. Outi Tornwall and Ms. Minttu Jussila (DNA biobanking). The authors would like to acknowledge the contribution of the late Academian of Science Leena Peltonen. Orkney Complex Disease Study (ORCADES): DNA extractions were performed at the Wellcome Trust Clinical Research Facility in Edinburgh. We would like to acknowledge the invaluable contributions of the research nurses in Orkney, the administrative team in Edinburgh and the people of Orkney. HA was supported by R21HG007687. SJL was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. MDT, LVW. and MSA were supported by the National Institute for Health Research (NIHR). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. MDT holds a Medical Research Council Senior Clinical Fellowship (G0902313). PAC and DBH were supported by R21HL125574. JFW was supported by the Chief Scientist Office of the Scottish Government (CZB/4/276, CZB/4/710) and the EU FP6 (LSHG-CT-2006-018947). MRJ was supported by the National Public Health Institute, the Biomedicum Helsinki, Finland, the Academy of Finland, and the Biocentrum Helsinki. JHZ was supported by the Medical Research Council, the Cancer Research UK, the European Union, the Stroke Association, the British Heart Foundation, the Department of Health, the Food Standards Agency and the Wellcome Trust. JK was supported by the Academy of Finland (265240, 263278). IPH’s research is funded by the MRC (G1000861). The UKLHS is led by the Institute for Social and Economic Research at the University of Essex and funded by the Economic and Social Research Council. The survey was conducted by NatCen, and the genome-wide scan data were analyzed and deposited by the Wellcome Trust Sanger Institute. Information on how to access the data can be found on the Understanding Society website, The UKLHS includes authors Michaela Benzeval, Jonathan Burton, Nicholas Buck, Annette Jäckle, Meena Kumari, Heather Laurie, Peter Lynn, Stephen Pudney, and Birgitta Rabe from the Institute for Social and Economic Research; and Dieter Wolke from University of Warwick.
EU Grant Number: (633595) DYNAHEALTH - Understanding the dynamic determinants of glucose homeostasis and social capability to promote Healthy and active aging
(277849) EURHEALTHAGEING - European ResearcH on DevElopmentAL, BirtH and Genetic Determinants of Ageing
Academy of Finland Grant Number: 104781
Detailed Information: 104781 (Academy of Finland Funding decision)
120315 (Academy of Finland Funding decision)
129269 (Academy of Finland Funding decision)
1114194 (Academy of Finland Funding decision)
24300796 (Academy of Finland Funding decision)
285547 (Academy of Finland Funding decision)
265240 (Academy of Finland Funding decision)
263278 (Academy of Finland Funding decision)
Dataset Reference: Supplementary data are available at IJE online.
Copyright information: © The Author 2017. Published by Oxford University Press on behalf of the International Epidemiological Association This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.