Paul Brennan, Simona Ognjanovic, Angela Cox, David C Christiani, Thomas Muley, Kim Overvad, Richard Houlston, Anush Mukeria, Vladimir Janout, Tadeusz M Orlowski, Beata Swiatkowska, William S Bush, David Zaridze, Ciprian Bolca, Loic Le Marchand, Yafang Li, James D McKay, Melinda C Aldrich, Ivana Holcatova, Rayjean J Hung, Lambertus A Kiemeney, Heike Bickeböller, Rosario Tumino, Xiangjun Xiao, Eric B Haura, Natasha Leighl, Xifeng Wu, Stig E Bojesen, Kjell Grankvist, Susanne M Arnold, Mattias Johansson, Olle Melander, Matthew B Schabath, Geoffrey Liu, Milica Kontic, Frances A Shepherd, Shanbeh Zienolddiny, M Dawn Teare, Judith Manz, Stephen Lam, Angela C Pesatori, Younghun Han, Chu Chen, John K Field, Mikael Johansson, Jonas Manjer, Pier Alberto Bertazzi, Antonia Trichopoulou, Michael W Marcus, Philip Lazarus, Adonina Tardon, Penella Woll, Matt Barnett, H-Erich Wichmann, David C Muller, Vidar Skaug, Jolanta Lissowska, David Qian, Demetrios Albanes, Ghislaine Scelo, Gary Goodman, Lesley M Butler, Per Bakke, Fiona Taylor, Olga Gorlova, Gad Rennert, María Soler Artigas, Angela Risch, Neil Caporaso, Angeline S Andrew, Christopher I Amos, Albert Rosenberger, Jakob S Johansen, Aage Haugen, Hans Brunnström, Eric J Duell
Non-small cell lung cancer (NSCLC) 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 SNPs and smoking status (never vs 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 NSCLC cases. Candidate SNPs with p-value less than 0.001 were further analyzed using a standard case-control interaction analysis including 13970 controls. The significant SNPs with p-value less than 3.5x10-5 (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 NSCLC 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 6.96x10-7 and 1.37 with 3.49x10-7, respectively. Additionally, interaction of smoking with rs4751674 was identified in squamous cell lung carcinoma with an odds ratio of 0.58 and p-value of 8.12x10-7. 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.