Journal article
Different diabetes types and pancreatic ductal adenocarcinoma: a Mendelian randomization and pathway/gene-set analysis
JNCI : Journal of the National Cancer Institute, Vol.118(3), pp.437-447
03/01/2026
DOI: 10.1093/jnci/djaf308
PMID: 41206949
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), 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.
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.
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.
Details
- Title: Subtitle
- Different diabetes types and pancreatic ductal adenocarcinoma: a Mendelian randomization and pathway/gene-set analysis
- Creators
- Ting Zhang - National Cancer InstituteXing Hua - Frederick National Laboratory for Cancer ResearchChirayu Mohindroo - National Cancer InstituteXiaoyu Wang - Frederick National Laboratory for Cancer ResearchDiptavo Dutta - National Cancer InstituteJia Liu - Frederick National Laboratory for Cancer ResearchShilpa Katta - Frederick National Laboratory for Cancer ResearchShengchao A Li - Frederick National Laboratory for Cancer ResearchJiahui Wang - Frederick National Laboratory for Cancer ResearchSamuel O Antwi - Mayo Clinic in FloridaAlan A Arslan - New York UniversityLaura E Beane Freeman - Division of Cancer Epidemiology and GeneticsPaige M Bracci - University of California, San FranciscoFederico Canzian - German Cancer Research CenterMengmeng Du - Memorial Sloan Kettering Cancer CenterSteven Gallinger - Lunenfeld-Tanenbaum Research InstitutePhyllis J Goodman - Fred Hutch Cancer CenterVerena Katzke - German Cancer Research CenterCharles Kooperberg - Fred Hutch Cancer CenterLoic Le Marchand - University of Hawaii SystemRachel E Neale - School of Public Health, University of Queensland, Brisbane, QLD, AustraliaAlpa V Patel - American Cancer SocietySandra Perdomo - Centre international de recherche sur le cancerXiao-Ou Shu - Vanderbilt UniversityKala Visvanathan - Johns Hopkins UniversityStephen K Van Den Eeden - Kaiser PermanenteEmily White - Fred Hutch Cancer CenterWei Zheng - Vanderbilt UniversityDemetrius Albanes - National Cancer InstituteGabriella Andreotti - National Cancer InstituteWilliam R Bamlet - Mayo Clinic in FloridaPaul Brennan - Centre international de recherche sur le cancerJulie E Buring - Harvard UniversityStephen J Chanock - National Cancer InstituteYu Chen - NYU Langone HealthBurcu Darst - Fred Hutch Cancer CenterPietro Ferrari - Centre international de recherche sur le cancerEdward L Giovannucci - Harvard UniversityMichael Goggins - Johns Hopkins UniversityChristopher Haiman - University of Southern CaliforniaManal Hassan - The University of Texas MD Anderson Cancer CenterElizabeth A Holly - University of California, San FranciscoRayjean J Hung - Lunenfeld-Tanenbaum Research InstituteMiranda R Jones - Johns Hopkins UniversityPeter Kraft - National Cancer InstituteRobert C Kurtz - Memorial Sloan Kettering Cancer CenterNúria Malats - Spanish National Cancer Research CentreSteven C Moore - National Cancer InstituteKimmie Ng - Dana-Farber Cancer InstituteAnn L Oberg - Mayo Clinic in FloridaIrene Orlow - Memorial Sloan Kettering Cancer CenterUlrike Peters - Fred Hutch Cancer CenterMiquel Porta - Universitat Autònoma de BarcelonaKari G Rabe - Mayo Clinic in FloridaNathaniel Rothman - Division of Cancer Epidemiology and GeneticsMaria-José Sánchez - CIBERESP Group on Cancer Epidemiology and Preventionm, CIBERESP, Madrid, SpainHoward D Sesso - Brigham and Women's HospitalDebra T Silverman - National Cancer InstituteMelissa C Southey - Cancer Council VictoriaCaroline Y Um - American Cancer SocietyJames Yarmolinsky - Imperial College LondonHerbert Yu - University of Hawaiʻi at MānoaChen Yuan - Dana-Farber Cancer InstituteJun Zhong - National Cancer InstituteBrian M Wolpin - Dana-Farber Cancer InstituteHarvey A Risch - Yale UniversityLaufey T Amundadottir - National Cancer InstituteAlison P Klein - Johns Hopkins UniversityKai Yu - National Cancer InstituteHaoyu Zhang - National Cancer InstituteRachael Z Stolzenberg-Solomon - National Cancer Institute
- Resource Type
- Journal article
- Publication Details
- JNCI : Journal of the National Cancer Institute, Vol.118(3), pp.437-447
- DOI
- 10.1093/jnci/djaf308
- PMID
- 41206949
- ISSN
- 0027-8874
- eISSN
- 1460-2105
- Grant note
- 75N910D00024 / NIH HHS HHS P50 CA257911 / NCI NIH HHS Z99 CA999999 / Intramural NIH HHS NIH HHS Z01 CP010193 / Intramural NIH HHS P30 CA008748 / NCI NIH HHS ZIA CP010193 / Intramural NIH HHS 001 / World Health Organization
- Language
- English
- Date published
- 03/01/2026
- Academic Unit
- Internal Medicine
- Record Identifier
- 9985177931302771
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