Genome-wide interaction study of smoking behavior and non-small cell lung cancer risk in Caucasian population

Yafang Li, Xiangjun Xiao, Younghun Han, Olga Gorlova, David Qian, Natasha Leighl, Jakob S. Johansen, Matt Barnett, Chu Chen, Gary Goodman, Angela Cox, Fiona Taylor, Penella Woll, H. Erich Wichmann, Judith Manz, Thomas Muley, Angela Risch, Albert Rosenberger, Susanne M. Arnold, Eric B. HauraCiprian Bolca, Ivana Holcatova, Vladimir Janout, Milica Kontic, Jolanta Lissowska, Anush Mukeria, Simona Ognjanovic, Tadeusz M. Orlowski, Ghislaine Scelo, Beata Swiatkowska, David Zaridze, Per Bakke, Vidar Skaug, Shanbeh Zienolddiny, Eric J. Duell, Lesley M. Butler, Richard Houlston, María Soler Artigas, Kjell Grankvist, Mikael Johansson, Frances A. Shepherd, Michael W. Marcus, Hans Brunnström, Jonas Manjer, Olle Melander, David C. Muller, Kim Overvad, Antonia Trichopoulou, Rosario Tumino, Geoffrey Liu, Stig E. Bojesen, Xifeng Wu, Loic Le Marchand, Demetrios Albanes, Heike Bickeböller, Melinda C. Aldrich, William S. Bush, Adonina Tardon, Gad Rennert, M. Dawn Teare, John K. Field, Lambertus A. Kiemeney, Philip Lazarus, Aage Haugen, Stephen Lam, Matthew B. Schabath, Angeline S. Andrew, Pier Alberto Bertazzi, Angela C. Pesatori, David C. Christiani, Neil Caporaso, Mattias Johansson, James D. McKay, Paul Brennan, Rayjean J. Hung, Christopher I. Amos

Research output: Contribution to journalArticlepeer-review

26 Scopus citations


Non-small cell lung cancer is the most common type of lung cancer. Both environmental and genetic risk factors contribute to lung carcinogenesis. We conducted a genome-wide interaction analysis between single nucleotide polymorphisms (SNPs) and smoking status (never- versus ever-smokers) in a European-descent population. We adopted a two-step analysis strategy in the discovery stage: we first conducted a case-only interaction analysis to assess the relationship between SNPs and smoking behavior using 13 336 non-small cell lung cancer cases. Candidate SNPs with P-value <0.001 were further analyzed using a standard case-control interaction analysis including 13 970 controls. The significant SNPs with P-value <3.5 × 10-5 (correcting for multiple tests) from the case-control analysis in the discovery stage were further validated using an independent replication dataset comprising 5377 controls and 3054 non-small cell lung cancer cases. We further stratified the analysis by histological subtypes. Two novel SNPs, rs6441286 and rs17723637, were identified for overall lung cancer risk. The interaction odds ratio and meta-analysis P-value for these two SNPs were 1.24 with 6.96 × 10-7 and 1.37 with 3.49 × 10-7, respectively. In addition, interaction of smoking with rs4751674 was identified in squamous cell lung carcinoma with an odds ratio of 0.58 and P-value of 8.12 × 10-7. This study is by far the largest genome-wide SNP-smoking interaction analysis reported for lung cancer. The three identified novel SNPs provide potential candidate biomarkers for lung cancer risk screening and intervention. The results from our study reinforce that gene-smoking interactions play important roles in the etiology of lung cancer and account for part of the missing heritability of this disease.

Original languageEnglish
Pages (from-to)336-346
Number of pages11
Issue number3
StatePublished - Mar 8 2018

Bibliographical note

Funding Information:
and Prevention, Russian N.N. Blokhin Cancer Research Centre, Moscow 115478, Russia, 19International Organization for Cancer Prevention and Research, Belgrade 11070, Serbia, 20Department of Thoracic Surgery, National Institute of Tuberculosis and Lung Diseases, Warsaw 01-138, Poland, 21International Agency for Research on Cancer (IARC), Genetic Epidemiology Group, Lyon 69008, France, 22Department of Environmental Epidemiology, Nofer Institute of Occupational Medicine, Łódź 91-348, Poland, 23Department of Clinical Science, University of Bergen, Bergen N-5020, Norway, 24Department of Toxicology, National Institute of Occupational Health, Oslo 0363, Norway, 25Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Programme, Catalan Institute of Oncology (ICO-IDIBELL), Hospitalet de Llobregat 08908, Barcelona, Spain, 26University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA, 27The Institute of Cancer Research, London SM2 5NG, UK, 28Department of Health Sciences, Genetic Epidemiology Group, University of Leicester, Leicester LE1 7RH, UK, 29Genetic Epidemiology Group, Department of Health Sciences, Leicester Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester LE3 9QP, UK, 30Department of Medical Biosciences, Umeå University, Umeå 901 85, Sweden, 31Department of Radiation Sciences, Umeå University, Umeå 901 87, Sweden, 32Medical Oncology Toronto, Princess Margaret Hospital, Toronto, ON M5G 2M9, Canada, 33Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool L69 3BX, UK, 34Department of Clinical Sciences, Lund University, Lund 221 00, Sweden, 35Department of Internal Medicine, Skåne University Hospital, Malmö 2005 02, Sweden, 36Department of Epidemiology and Biostatistics, Imperial College London, St Mary’s Campus, London W2 1PG, UK, 37Section for Epidemiology, Department of Public Health, Aarhus University, DK-8000 Aarhus C, Denmark, 38Department of Hygiene and Epidemiology, Medical School, University of Athens, Athens 157 72, Greece, 39Molecular and Nutritional Epidemiology Unit, CSPO (Cancer Research and Prevention Centre), Scientific Institute of Tuscany, Florence 50141, Italy, 40Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada, 41Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark, 42Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark, 43Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen, Denmark, 44Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA, 45Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA, 46Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Bethesda, MD 20892, USA, 47Department of Genetic Epidemiology, University Medical Center, Georg-August University Göttingen, Göttingen 37073, Germany, 48Department of Thoracic Surgery, Division of Epidemiology, Vanderbilt University Medical Center, Nashville, TN 37232, USA, 49Department of Epidemiology and Biostatistics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA, 50Medicina, IUOPA-Universidad de Oviedo, 33003 Oviedo, Spain, 51Technion Faculty of Medicine, Clalit National Cancer Control Center, Carmel Medical Center, Haifa 3436212, Israel, 52Genetic Epidemiology, School of Health and Related Research, University of Sheffield, Sheffield S1 4DA, UK, 53Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3BX, UK, 54Department for Health Evidence, Radboud University Medical Center, Nijmegen 6525 EZ, Netherlands, 55Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, WA 99210, USA, 56Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada, 57Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA, 58Department of Epidemiology, Norris Cotton Cancer Center, Dartmouth College, Hanover, NH 03755, USA, 59Department of Preventive Medicine, IRCCS Foundation Cà Granda Ospedale, Maggiore Policlinico, University of Milan, 20122 Milan, Italy, 60Department of Clinical Sciences and Community Health–DISCCO, University of Milan, 20122 Milan, Italy, 61Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA, 62International Agency for Research on Cancer, World Health Organization, 69372 Lyon, France, 63Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Lunenfeld-Tanenbaum Research Institute, Toronto, Ontario M5G 1X5, Canada

Publisher Copyright:
© The Author(s) 2018. Published by Oxford University Press. All rights reserved.

ASJC Scopus subject areas

  • Cancer Research


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