Smoking Modifies Pancreatic Cancer Risk Loci on 2q21.3
Abstract
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 = 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 = 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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 11, 2021
- Source ID
- 10.1158/0008-5472.can-20-3267
Entities
People
- Alan A Arslan
- Alison P Klein
- Amanda Blackford
- Ana Babic
- Ann L Oberg
- Anne Tjønneland
- Anne Zeleniuch-jacquotte
- Antonia Trichopoulou
- Bas Bueno-de-Mesquita
- Brian M. Wolpin
- Charles Kooperberg
- Charles S. Fuchs
- Daniele Campa
- Debra T. Silverman
- Demetrius Albanes
- Donghui Li
- Edward L. Giovannucci
- Elio Riboli
- Elizabeth A. Holly
- Emily White
- Eric J Duell
- Eric J. Jacobs
- Erica J. Childs
- Evelina Mocci
- Fangcheng Yuan
- Federico Canzian
- Gabriella Andreotti
- Ghislaine Scelo
- Gloria M. Petersen
- Graham Giles
- Harvey A. Risch
- Herbert Yu
- Howard D Sesso
- I-min Lee
- Ian M. Thompson, Jr.
- J. Michael Gaziano
- Jean Wactawski-Wende
- Julie E. Buring
- Kala Visvanathan
- Kari G Rabe
- Kimmie Ng
- Laufey T. Amundadottir
- Laura E. Beane-freeman
- Loic Le Marchand
- Lynne R. Wilkens
- Manal M. Hassan
- Mengmeng Du
- Michael Goggins
- Miquel Porta
- Nathaniel Rothman
- Nicolas Wentzensen
- Nilanjan Chatterjee
- Nuria Malats
- Oliver Strobel
- Paige M. Bracci
- Patricia Hartge
- Paul Brennan
- Peter Kraft
- Peter R. Leavitt
- Phyllis J. Goodman
- Prosenjit Kundu
- Rachael Z. Stolzenberg-Solomon
- Rachel Neale
- Rayjean J Hung
- Robert C. Kurtz
- Robert N. Hoover
- Roger L. Milne
- Salvatore Panico
- Sonja I. Berndt
- Stephen Chanock
- Stephen K Van Den Eeden
- Steven Gallinger
- Ulrike Peters
- Victoria L. Stevens
- Wei Xing Zheng
- William Bamlet
- William Wheeler
- Xiao-Ou Shu
Organizations
- American Cancer Society
- Autonomous University of Barcelona
- California Department of Public Health
- Cancer Council Victoria
- Czech Science Foundation
- Dana–Farber Cancer Institute
- Division of Cancer Epidemiology and Genetics, National Cancer Institute
- European Cooperation in Science and Technology
- Federal Ministry of Research, Technology and Space
- Fred Hutchinson Cancer Center
- Generalitat of Catalonia
- German Cancer Research Center
- Harvard Medical School
- Harvard University
- Heidelberg University
- Imperial College London
- Johns Hopkins Bloomberg School of Public Health
- Johns Hopkins School of Medicine
- Leiden University Medical Center
- Lustgarten Foundation for Pancreatic Cancer Research
- Mayo Medical School
- Memorial Sloan Kettering Cancer Center
- Ministerio de Ciencia y Tecnología
- Ministry of Health of Italy
- Ministry of Health of the Czech Republic
- National Cancer Institute
- National Center for Oncological Research
- National Health and Medical Research Council
- National Human Genome Research Institute
- National Institutes of Health
- National and Kapodistrian University of Athens
- Netherlands National Institute for Public Health and the Environment
- Pancreatic Cancer Action Network
- Patient-Centered Outcomes Research Institute
- QIMR Berghofer Medical Research Institute
- United States Department of Defense
- United States Department of Health and Human Services
- Universiti Malaya
- University at Buffalo
- University of California, San Francisco
- University of Copenhagen
- University of Melbourne
- University of Naples Federico II
- University of Pisa
- University of Texas at Austin
- University of Toronto
- Vanderbilt University
- Yale School of Medicine
- Yale School of Public Health