Abstract 6209: Different types of diabetes and pancreatic ductal adenocarcinoma risk: A Mendelian randomization and pathway/gene-set analysis

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Abstract Objective: The associations between different types of diabetes, characterized by distinct pathophysiology and genetic architecture, and pancreatic ductal adenocarcinoma (PDAC) risk are not fully understood. We investigated associations of genetic susceptibility to type 2 diabetes (T2D), its eight mechanistic clusters and type 1 diabetes (T1D) using Mendelian randomization (MR) and maturity-onset diabetes of the young (MODY) pathway/gene-set analysis with PDAC risk. Method: Using summary-level genome-wide association statistics for T2D (242, 283 cases, 1, 569, 734 controls), T1D (18, 942 cases, 501, 638 controls), and PDAC (10, 244 cases and 360, 535 controls) in individuals of European ancestry, we conducted two-sample MR to examine associations of genetic susceptibility to T2D and T1D with PDAC risk, using single nucleotide polymorphisms (SNP) significantly associated with T2D, eight mechanistic TD2 clusters (i.e., β-cell dysfunction with a positive or negative association with proinsulin, residual glycaemic, body fat, metabolic syndrome, obesity, lipodystrophy, and liver and lipid metabolism), and T1D identified from published genome-wide association studies (P<5×10-8) as instrumental variables. We also assessed associations of genetic susceptibility to PDAC risk with T2D and T1D using reverse MR. We used MR-RAPS method as the primary analysis approach complemented with sensitivity analyses using MR-IVW, weighted-median, MR-Egger, MR-PRESSO and MR-PIVW. We applied the Summary-based Adaptive Rank Truncated Product (sARTP) method to evaluate the associations for PDAC and the MODY gene set, which consists of 26 genes identified from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Results: Genetic susceptibility to T2D (MR-RAPS: OR=1.10; 95% CI 1.05-1.14), particularly the obesity (OR=1.28; 95% CI 1.15-1.42) and lipodystrophy (OR=1.25; 95% CI 1.04-1.50) clusters, was associated with PDAC risk. T1D showed no association with PDAC risk (OR=1.01; 95% CI 0.99-1.02). Reverse MR found no evidence that genetic susceptibility to PDAC risk was associated with T2D or T1D (P>0.05). Sensitivity analyses using other MR methods supported these findings, with no evidence of pleiotropic effects (MR-Egger intercept P>0.05). The MODY gene-set was significantly associated with PDAC risk (P=2.5×10-6), with HNF1A, HNF1B, FOXA3, HNF4A, and HNF4G as the top five contributing genes. Conclusion: Our findings support a role of T2D, particularly the obesity and lipodystrophy clusters, in PDAC risk. Additionally, the genomic susceptibility regions of MODY were significantly associated with PDAC. Citation Format: Ting Zhang, Xing Hua, Chirayu Mohindroo, Xiaoyu Wang, PanScan and PanC4 Consortium, Brian M. Wolpin, Harvey A. Risch, Laufey T. Amundadottir, Alison P. Klein, Kai Yu, Haoyu Zhang, Rachael Z. Stolzenberg-Solomon. Different types of diabetes and pancreatic ductal adenocarcinoma risk: A Mendelian randomization and pathway/gene-set analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6209.