| Literature DB >> 33574088 |
Evelina Mocci1, Prosenjit Kundu2, Nilanjan Chatterjee2,3, Alison P Klein4,5,6, Rachael Stolzenberg-Solomon7, William Wheeler8, Alan A Arslan9,10,11, Laura E Beane-Freeman3, Paige M Bracci12, Paul Brennan13, Federico Canzian14, Mengmeng Du15, Steven Gallinger16, Graham G Giles17,18,19, Phyllis J Goodman20, Charles Kooperberg21, Loic Le Marchand22, Rachel E Neale23, Xiao-Ou Shu24, Kala Visvanathan1,5, Emily White25, Wei Zheng24, Demetrius Albanes3, Gabriella Andreotti3, Ana Babic26, William R Bamlet27, Sonja I Berndt3, Amanda L Blackford1, Bas Bueno-de-Mesquita28,29,30,31, Julie E Buring32,33, Daniele Campa34, Stephen J Chanock3, Erica J Childs1, Eric J Duell35, Charles S Fuchs36,37,38, J Michael Gaziano33,39, Edward L Giovannucci32,40,41, Michael G Goggins6, Patricia Hartge3, Manal M Hassan42, Elizabeth A Holly12, Robert N Hoover3, Rayjean J Hung16, Robert C Kurtz43, I-Min Lee32,33, Núria Malats44, Roger L Milne17,18,19, Kimmie Ng26, Ann L Oberg27, Salvatore Panico45, Ulrike Peters25, Miquel Porta46,47, Kari G Rabe27, Elio Riboli30, Nathaniel Rothman3, Ghislaine Scelo13, Howard D Sesso32,33, Debra T Silverman3, Victoria L Stevens48, Oliver Strobel49, Ian M Thompson50, Anne Tjonneland51, Antonia Trichopoulou52, Stephen K Van Den Eeden53, Jean Wactawski-Wende54, Nicolas Wentzensen3, Lynne R Wilkens22, Herbert Yu22, Fangcheng Yuan3, Anne Zeleniuch-Jacquotte10,11, Laufey T Amundadottir3, Donghui Li42, Eric J Jacobs51, Gloria M Petersen27, Brian M Wolpin26, Harvey A Risch55, Peter Kraft32,56.
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, P interaction = 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 (r 2 = 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. SIGNIFICANCE: This large genome-wide interaction study identifies a susceptibility locus on 2q21.3 that significantly modified PDAC risk by smoking status, providing insight into smoking-associated PDAC, with implications for prevention. ©2021 American Association for Cancer Research.Entities:
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Year: 2021 PMID： 33574088 PMCID： PMC8178175 DOI： 10.1158/0008-5472.CAN-20-3267
Source DB: PubMed Journal: Cancer Res ISSN： 0008-5472 Impact factor: 13.312