Smoking modifies pancreatic cancer risk loci on 2q21.3.
Mocci E, Kundu P, Wheeler W, Arslan AA, Beane Freeman LE, Bracci PM, Brennan P, Canzian F, Du M, Gallinger S, Giles GG, Goodman PJ, Kooperberg C, Le Marchand L, Neale RE, Shu XO, Visvanathan K, White E, Zheng W, Albanes D, Andreotti G, Babic A, Bamlet WR, Berndt SI, Blackford AL, Bueno-de-Mesquita B, Buring JE, Campa D, Chanock SJ, Childs EJ, Duell EJ, Fuchs CS, Gaziano JM, Giovannucci EL, Goggins MG, Hartge P, Hassan MM, Holly EA, Hoover RN, Hung RJ, Kurtz RC, Lee IM, Malats N, Milne RL, Ng K, Oberg AL, Panico S, Peters U, Porta M, Rabe KG, Riboli E, Rothman N, Scelo G, Sesso HD, Silverman DT, Stevens VL, Strobel O, Thompson IM, Tjonneland A, Trichopoulou A, Van Den Eeden SK, Wactawski-Wende J, Wentzensen N, Wilkens LR, Yu H, Yuan F, Zeleniuch-Jacquotte A, Amundadottir LT, Li D, Jacobs EJ, Petersen GM, Wolpin BM, Risch HA, Kraft P, Chatterjee N, Klein AP, Stolzenberg-Solomon RZ
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 if there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and P-values < 5 x 10-8 were 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 which included 45 significantly associated SNPs, was rs1818613 (per allele OR in never smokers 0.87, 95% 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, interaction P-value=3.08x10-9). 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 LD 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.
- 2006-0306: Whole Genome Scan of Incident Pancreatic Cancer in the Cohort Consortium (PanScan) (Rachael Stolzenberg-Solomon - 2006)