Smoking modifies pancreatic cancer risk loci on 2q21.3

Evelina Mocci, Prosenjit Kundu, William Wheeler, Alan A. Arslan, Laura E. Beane-Freeman, Paige M. Bracci, Paul Brennan, Federico Canzian, Mengmeng Du, Steven Gallinger, Graham G. Giles, Phyllis J. Goodman, Charles Kooperberg, Loic Le Marchand, Rachel E. Neale, Xiao Ou Shu, Kala Visvanathan, Emily White, Wei Zheng, Demetrius AlbanesGabriella Andreotti, Ana Babic, William R. Bamlet, Sonja I. Berndt, Amanda L. Blackford, Bas Bueno-De-Mesquita, Julie E. Buring, Daniele Campa, Stephen J. Chanock, Erica J. Childs, Eric J. Duell, Charles S. Fuchs, J. Michael Gaziano, Edward L. Giovannucci, Michael G. Goggins, Patricia Hartge, Manal M. Hassan, Elizabeth A. Holly, Robert N. Hoover, Rayjean J. Hung, Robert C. Kurtz, I. Min Lee, Nuria Malats, Roger L. Milne, Kimmie Ng, Ann L. Oberg, Salvatore Panico, Ulrike Peters, Miquel Porta, Kari G. Rabe, Elio Riboli, Nathaniel Rothman, Ghislaine Scelo, Howard D. Sesso, Debra T. Silverman, Victoria L. Stevens, Oliver Strobel, Ian M. Thompson, Anne Tjonneland, Antonia Trichopoulou, Stephen K. van Den Eeden, Jean Wactawski-Wende, Nicolas Wentzensen, Lynne R. Wilkens, Herbert Yu, Fangcheng Yuan, Anne Zeleniuch-Jacquotte, Laufey T. Amundadottir, Donghui Li, Eric J. Jacobs, Gloria M. Petersen, Brian M. Wolpin, Harvey A. Risch, Peter Kraft, Nilanjan Chatterjee, Alison P. Klein, Rachael Stolzenberg-Solomon

Research output: Contribution to journalArticlepeer-review


Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine whether there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and P < 5 10-8 was considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region that included 45 significantly associated SNPs, was rs1818613 [per allele OR in never smokers 0.87, 95% confidence interval (CI), 0.82-0.93; former smokers 1.00, 95% CI, 0.91-1.07; current smokers 1.25, 95% CI 1.12-1.40, Pinteraction ¼ 3.08 10-9). Examination of the Genotype-Tissue Expression Project data demonstrated an expression quantitative trait locus in this region for TMEM163 and CCNT2 in several tissue types. Colocalization analysis supported a shared SNP, rs842357, in high linkage disequilibrium with rs1818613 (r2 ¼ 0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings.

Original languageEnglish (US)
Pages (from-to)3134-3143
Number of pages10
JournalCancer research
Issue number11
StatePublished - Jun 1 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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