Journal Article

DKFZ-2025-02358

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Different diabetes types and pancreatic ductal adenocarcinoma: a Mendelian randomization and pathway/gene-set analysis.

Zhang, T. ; Hua, X. ; Mohindroo, C. ; Wang, X. ; Dutta, D. ; Liu, J. ; Katta, S. ; Li, S. A. ; Wang, J. ; Antwi, S. O. ; Arslan, A. A. ; Beane Freeman, L. E. ; Bracci, P. M. ; Canzian, F.DKFZ* ; Du, M. ; Gallinger, S. ; Goodman, P. J. ; Katzke, V.DKFZ* ; Kooperberg, C. ; Le Marchand, L. ; Neale, R. E. ; Patel, A. V. ; Perdomo, S. ; Shu, X.-O. ; Visvanathan, K. ; Van Den Eeden, S. K. ; White, E. ; Zheng, W. ; Albanes, D. ; Andreotti, G. ; Bamlet, W. R. ; Brennan, P. ; Buring, J. E. ; Chanock, S. J. ; Chen, Y. ; Darst, B. ; Ferrari, P. ; Giovannucci, E. L. ; Goggins, M. ; Haiman, C. ; Hassan, M. ; Holly, E. A. ; Hung, R. J. ; Jones, M. R. ; Kraft, P. ; Kurtz, R. C. ; Malats, N. ; Moore, S. C. ; Ng, K. ; Oberg, A. L. ; Orlow, I. ; Peters, U. ; Porta, M. ; Rabe, K. G. ; Rothman, N. ; Sánchez, M.-J. ; Sesso, H. D. ; Silverman, D. T. ; Southey, M. C. ; Um, C. Y. ; Yarmolinsky, J. ; Yu, H. ; Yuan, C. ; Zhong, J. ; Wolpin, B. M. ; Risch, H. A. ; Amundadottir, L. T. ; Klein, A. P. ; Yu, K. ; Zhang, H. ; Stolzenberg-Solomon, R. Z.

2025
Oxford Univ. Press Oxford

Abstract: The associations between different types of diabetes, characterized by distinct pathophysiology and genetic architecture, and pancreatic ductal adenocarcinoma (PDAC) risk are not understood.We investigated associations of genetic susceptibility to type 2 diabetes (T2D), eight 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.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 1.05-1.15), particularly the T2D obesity (OR = 1.28; 95% CI 1.15-1.42) and lipodystrophy (OR = 1.25; 95% CI 1.03-1.51) clusters. No association was observed for T1D with PDAC risk (OR = 1.01; 95% CI 0.99-1.02). 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.Our results from this genetic association study support that T2D, particularly the obesity and lipodystrophy mechanistic clusters, and MODY genomic susceptibility regions play a role in the etiology of PDAC.

Keyword(s): Maturity-onset diabetes of the young ; Mendelian Randomization ; Pancreatic ductal adenocarcinoma ; Type 1 Diabetes ; Type 2 Diabetes

Note: ISSN 1460-2105 / epub

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Contributing Institute(s):

1. Genomische Epidemiologie (C055)
2. Epidemiologie von Krebs (C020)

Research Program(s):

1. 313 - Krebsrisikofaktoren und Prävention (POF4-313) (POF4-313)

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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