Different diabetes types and pancreatic ductal adenocarcinoma: a Mendelian randomization and pathway/gene-set analysis

作者：Ting Zhang, Xing Hua, Chirayu Mohindroo, Xiaoyu Wang, Diptavo Dutta, Jia Liu, Shilpa Katta, Shengchao A. Li, Jiahui Wang, Samuel O. Antwi, Alan A. Arslan, Laura E. Beane Freeman, Paige M. Bracci, Federico Canzian, Mengmeng Du, Steven Gallinger, Phyllis J. Goodman, Verena Katzke, Charles Kooperberg, Loı̈c Le Marchand, Rachel Ε. Neale, Alpa V. Patel, Sandra Pérdomo, Xiao-Ou Shu, Kala Visvanathan, Stephen K. Van Den Eeden, Emily White, Wei Zheng, Demetrius Albanes, Gabriella Andreotti, William R. Bamlet, Paul Brennan, Julie E. Buring, Stephen J. Chanock, Yu Chen, Burcu F. Darst, Pietro Ferrari, Edward L. Giovannucci, Michael Goggins, Christopher A. Haiman, Manal M. Hassan, Elizabeth A. Holly, Rayjean J. Hung, Miranda R. Jones, Peter Kraft, Robert C. Kurtz, Núria Malats, Steven C. Moore, Kimmie Ng, Ann L. Oberg, Irene Orlow, Ulrike Peters, Miquel Porta, Kari G. Rabe, Nathaniel Rothman, María‐José Sánchez, Howard D. Sesso, Debra T. Silverman, Melissa C. Southey, Caroline Y. Um, James Yarmolinsky, Herbert Yu, Chen Yuan, Jun Zhong, Brian M. Wolpin, Harvey A. Risch, Laufey T. Ámundadóttir, Alison P. Klein, Kai Yu, Haoyu Zhang, Rachael Z. Stolzenberg‐Solomon · 发表于：JNCI Journal of the National Cancer Institute · 年份：2025 · DOI：10.1093/jnci/djaf308 · 被引用次数：1 · 研究领域：Genetic Associations and Epidemiology、Adipokines, Inflammation, and Metabolic Diseases、Pancreatic and Hepatic Oncology Research

BACKGROUND: The associations between different types of diabetes, characterized by distinct pathophysiology and genetic architecture, and pancreatic ductal adenocarcinoma (PDAC) risk are not understood. METHODS: We investigated associations of genetic susceptibility to type 2 diabetes (T2D), 8 T2D mechanistic clusters, type 1 diabetes (T1D), and maturity-onset diabetes of the young (MODY) with PDAC risk. We used genome-wide association study (GWAS) summary-level 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. RESULTS: Two-sample Mendelian randomization (MR) using the Robust Adjusted Profile Score (MR-RAPS) method indicated that genetically predicted T2D was associated with PDAC risk (OR = 1.10; 95% CI = 1.05 to 1.15), particularly the T2D obesity (OR = 1.28; 95% CI = 1.15 to 1.42) and lipodystrophy (OR = 1.25; 95% CI = 1.03 to 1.51) clusters. No association was observed for T1D with PDAC risk (OR = 1.01; 95% CI = 0.99 to 1.02). Pathway/gene-set analysis using the summary-based Adaptive Rank Truncated Product (sARTP) method revealed a significant association between the MODY gene-sets and PDAC risk (P = 1.5 × 10-8), which remained after excluding 20 known PDAC GWAS loci (P = 7.6 × 10-4). HNF1A, FOXA3, and HNF4A were the top contributing genes after excluding the previously identified GWAS loci regions. CONCLUSIONS: Our results from this genetic associ...