Περίληψη:
Background: Obesity and diabetes are major modifiable risk factors for pancreatic cancer. Interactions between genetic variants and diabetes/obesity have not previously been comprehensively investigated in pancreatic cancer at the genome-wide level. Methods: We conducted a gene–environment interaction (GxE) analysis including 8,255 cases and 11,900 controls from four pancreatic cancer genome-wide association study (GWAS) datasets (Pancreatic Cancer Cohort Consortium I–III and Pancreatic Cancer Case Control Consortium). Obesity (body mass index ≥30 kg/m2) and diabetes (duration ≥3 years) were the environmental variables of interest. Approximately 870,000 SNPs (minor allele frequency ≥0.005, genotyped in at least one dataset) were analyzed. Case–control (CC), case-only (CO), and joint-effect test methods were used for SNP-level GxE analysis. As a complementary approach, gene-based GxE analysis was also performed. Age, sex, study site, and principal components accounting for population substructure were included as covariates. Meta-analysis was applied to combine individual GWAS summary statistics. Results: No genome-wide significant interactions (departures from a log-additive odds model) with diabetes or obesity were detected at the SNP level by the CC or CO approaches. The joint-effect test detected numerous genome-wide significant GxE signals in the GWAS main effects top hit regions, but the significance diminished after adjusting for the GWAS top hits. In the gene-based analysis, a significant interaction of diabetes with variants in the FAM63A (family with sequence similarity 63 member A) gene (significance threshold P < 1.25 106) was observed in the meta-analysis (PGxE ¼ 1.2 106, PJoint ¼ 4.2 107). Conclusions: This analysis did not find significant GxE interactions at the SNP level but found one significant interaction with diabetes at the gene level. A larger sample size might unveil additional genetic factors via GxE scans. Impact: This study may contribute to discovering the mechanism of diabetes-associated pancreatic cancer. © 2020 American Association for Cancer Research.
Συγγραφείς:
Tang, H.
Jiang, L.
Stolzenberg-Solomon, R.Z.
Arslan, A.A.
Beane Freeman, L.E.
Bracci, P.M.
Brennan, P.
Canzian, F.
Du, M.
Gallinger, S.
Giles, G.G.
Goodman, P.J.
Kooperberg, C.
Le Marchand, L.
Neale, R.E.
Shu, X.-O.
Visvanathan, K.
White, E.
Zheng, W.
Albanes, D.
Andreotti, G.
Babic, A.
Bamlet, W.R.
Berndt, S.I.
Blackford, A.
Bueno-De-Mesquita, B.
Buring, J.E.
Campa, D.
Chanock, S.J.
Childs, E.
Duell, E.J.
Fuchs, C.
Michael Gaziano, J.
Goggins, M.
Hartge, P.
Hassam, M.H.
Holly, E.A.
Hoover, R.N.
Hung, R.J.
Kurtz, R.C.
Lee, I.-M.
Malats, N.
Milne, R.L.
Ng, K.
Oberg, A.L.
Orlow, I.
Peters, U.
Porta, M.
Rabe, K.G.
Rothman, N.
Scelo, G.
Sesso, H.D.
Silverman, D.T.
Thompson, I.M.
Tjønneland, A.
Trichopoulou, A.
Wactawski-Wende, J.
Wentzensen, N.
Wilkens, L.R.
Yu, H.
Zeleniuch-Jacquotte, A.
Amundadottir, L.T.
Jacobs, E.J.
Petersen, G.M.
Wolpin, B.M.
Risch, H.A.
Chatterjee, N.
Klein, A.P.
Li, D.
Kraft, P.
Wei, P.
