Abstract 1295: Genomewide gene-diabetes and gene-obesity interaction scan in 7095 cases and 10710 controls from Pancreatic Cancer Cohort Consortium and Pancreatic Cancer Case Control Consortium
Authors: Tang Hongwei , Jiang Lai , Amundadottir Laufey T. , Risch Harvey A. , Stolzenberg-Solomon Rachael S. , Klein Alison P. , Wolpin Brian M. , Petersen Gloria , Chatterjee Nilanjan , Li Donghui , Kraft Peter , Wei Peng 
Published: July 2017

Introduction: Obesity and diabetes are two major modifiable risk factors for pancreatic cancer. Genetic variation affecting the risk of obesity- and diabetes-related pancreatic cancer have yet to be comprehensively investigated at the genome-wide level.

Aims: To identify novel gene-environment interactions (GxE) of obesity/diabetes on pancreatic cancer risk.

Methods: We conducted a multi-stage genome-wide gene-diabetes and gene-obesity interaction study using GWAS data of 7095 cases and 10710 controls from Pancreatic Cancer Consortium (PanScan I, PanScan II and PanScan III) and Pancreatic Cancer Case Control Consortium (PanC4). About 870,000 SNPs, having MAF ≥ 0.005 and having been genotyped in at least one study, were analyzed. Missing genotypes were imputed using IMPUTE2 and the Haplotype Reference Consortium (HRC) reference panel. Case-control (CC) and case-only (CO) methods were used for SNP-level GxE analysis. Fixed-, random- and joint-effect models built in “rareGE” R package were used for gene-based GxE analysis. About 20,000 genes that have at least one SNP genotyped were included in the analysis. Age, gender and principal components accounting for subpopulation structure were adjusted in both SNP-level and gene-level analyses. Obesity was defined as body mass index ≥30 mg/m2. Diabetics with &lt;3-year duration were excluded for gene-diabetes interaction analysis. The PanScan I, II, III and PanC4 datasets were analyzed separately followed by meta-analysis of the summary statistics. Fixed-effect and Fisher’s p-value based meta-analysis was applied for SNP-level and gene-level GxE analysis, respectively.

Results: No genome-wide significant (P&lt;5 x 10-8 ) interaction at the SNP level was detected in any of the PanScan or PanC4 datasets or in the meta-analysis. A significant interaction of diabetes and FAM63A (family with sequence similarity 63 member A) gene (P&lt;2.5 x 10-6) was observed in the meta-analysis (PFixed= 3.4 x 10-5, PRandom= 1.9 x 10-6, PJoint= 6.8 x 10-7) . This interaction showed nominal significance in all individual dataset analyses. The corresponding P values for this interaction were 4.2 x 10-2, 3.8 x 10-2 and 6.8 x 10-2 in PanScan I, 2.8 x 10-2, 3.9 x 10-2 and 6.5 x 10-2 9.1 x 10-3, 2.2 x 10-4 and 8.8 x 10-6 in PanScan III, and 3.1 x 10-3, 3.4 x 10-3 and 8.8 x 10-3 in PanC4, respectively.

Conclusions: In the largest genome-wide GxE analysis for pancreatic cancer to date, we identified a significant diabetes interacting gene in pancreatic cancer, which was consistently replicated in 4 individual GWAS studies. This observation identifies FAM63A as a candidate for future functional studies to understand its role in pancreatic cancer etiology. Further increasing the sample size may unveil additional genetic loci that contribute to the susceptibility to pancreatic cancer via G x E.

Citation Format: Hongwei Tang, Lai Jiang, Laufey T. Amundadottir, Harvey A. Risch, Rachael S. Stolzenberg-Solomon, Alison P. Klein, Brian M. Wolpin, Gloria Petersen, Nilanjan Chatterjee, Donghui Li, Peter Kraft, Peng Wei. Genomewide gene-diabetes and gene-obesity interaction scan in 7095 cases and 10710 controls from Pancreatic Cancer Cohort Consortium and Pancreatic Cancer Case Control Consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1295. doi:10.1158/1538-7445.AM2017-1295