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. 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.

Type 2 diabetes prevention diet and the risk of pancreatic cancer: A large prospective multicenter study

“…Indeed, a cross-sectional studies found that ever smoking was associated with higher adherence to Mediterranean diet [41]. An alternative explanation may be the potential interaction between adherence to type 2 diabetes prevention diet and smoking in the etiological pathway to pancreatic cancer, given that smoking has been causally associated with the occurrence of this cancer [42,43]. Importantly, we cannot rule out the possibility that the above difference in the risk of pancreatic cancer between subgroups is a chance finding, though it is mechanistically possible.…”

Body mass index, C-reactive protein, and pancreatic cancer: A Mendelian randomization analysis to investigate causal pathways

“…The remaining 458 SNPs of BMI-related genetic variation that simultaneously meet assumptions 1, 2, and 3 were screened from the human genotype–phenotype association database; meanwhile, the SNPs related to smoking ( 26 ) (rs10927006, rs3845344, rs12089815, rs2568958, rs34517439, rs6545714, rs10182416, rs9876664, rs78605811, rs9835772, rs1454687, rs75499503, rs74750282, rs3901286, rs215634, rs12541408, rs7024334, rs11012732, rs6265, rs317656, rs7132908, rs9515446, rs862320, rs9926784, and rs35154326) were deleted. As the aforementioned 25 SNPs were removed, only 433 were retained.…”

Pancreatic Cancer: Challenges and Opportunities in Locoregional Therapies

“…More importantly, smoking accounts for 14% of the population attributed risk (PAR) compared to other risk factors such as alcohol abuse, body mass index, food, and physical exercise [ 14 ]. A genome study of 7937 pancreatic ductal adenocarcinoma (PDAC) cases in 2021 reported a genomic locus that significantly increased PDAC risk with smoking [ 15 ]. Furthermore, multiple studies have proven that smokers are at double the risk for PC compared to non-smokers [ 16 , 17 ].…”