Hepcidin-regulating iron metabolism genes and pancreatic ductal adenocarcinoma: A pathway analysis of genome-wide association studies

Sachelly Julián-Serrano, Fangcheng Yuan, William Wheeler, Beben Benyamin, Mitchell J. Machiela, Alan A. Arslan, Laura E. Beane-Freeman, Paige M. Bracci, Eric J. Duell, Mengmeng Du, Steven Gallinger, Graham G. Giles, Phyllis J. Goodman, Charles Kooperberg, Loic Le Marchand, Rachel E. Neale, Xiao Ou Shu, Stephen K. Van Den Eeden, Kala Visvanathan, Wei ZhengDemetrius Albanes, Gabriella Andreotti, Eva Ardanaz, Ana Babic, Sonja I. Berndt, Lauren K. Brais, Paul Brennan, Bas Bueno-De-Mesquita, Julie E. Buring, Stephen J. Chanock, Erica J. Childs, Charles C. Chung, Eleonora Fabiánová, Lenka Foretová, Charles S. Fuchs, J. Michael Gaziano, Manuel Gentiluomo, Edward L. Giovannucci, Michael G. Goggins, Thilo Hackert, Patricia Hartge, Manal M. Hassan, Ivana Holcátová, Elizabeth A. Holly, Rayjean I. Hung, Vladimir Janout, Robert C. Kurtz, I. Min Lee, Núria Malats, David McKean, Roger L. Milne, Christina C. Newton, Ann L. Oberg, Sandra Perdomo, Ulrike Peters, Miquel Porta, Nathaniel Rothman, Matthias B. Schulze, Howard D. Sesso, Debra T. Silverman, Ian M. Thompson, Jean Wactawski-Wende, Elisabete Weiderpass, Nicolas Wenstzensen, Emily White, Lynne R. Wilkens, Herbert Yu, Anne Zeleniuch-Jacquotte, Jun Zhong, Peter Kraft, Dounghui Li, Peter T. Campbell, Gloria M. Petersen, Brian M. Wolpin, Harvey A. Risch, Laufey T. Amundadottir, Alison P. Klein, Kai Yu, Rachael Z. Stolzenberg-Solomon

Research output: Contribution to journalArticlepeer-review


Background: Epidemiological studies have suggested positive associations for iron and red meat intake with risk of pancreatic ductal adenocarcinoma (PDAC). Inherited pathogenic variants in genes involved in the hepcidin-regulating iron metabolism pathway are known to cause iron overload and hemochromatosis. Objectives: The objective of this study was to determine whether common genetic variation in the hepcidin-regulating iron metabolism pathway is associated with PDAC. Methods: We conducted a pathway analysis of the hepcidin-regulating genes using single nucleotide polymorphism (SNP) summary statistics generated from 4 genome-wide association studies in 2 large consortium studies using the summary data-based adaptive rank truncated product method. Our population consisted of 9253 PDAC cases and 12,525 controls of European descent. Our analysis included 11 hepcidin-regulating genes [bone morphogenetic protein 2 (BMP2), bone morphogenetic protein 6 (BMP6), ferritin heavy chain 1 (FTH1), ferritin light chain (FTL), hepcidin (HAMP), homeostatic iron regulator (HFE), hemojuvelin (HJV), nuclear factor erythroid 2-related factor 2 (NRF2), ferroportin 1 (SLC40A1), transferrin receptor 1 (TFR1), and transferrin receptor 2 (TFR2)] and their surrounding genomic regions (±20 kb) for a total of 412 SNPs. Results: The hepcidin-regulating gene pathway was significantly associated with PDAC (P = 0.002), with the HJV, TFR2, TFR1, BMP6, and HAMP genes contributing the most to the association. Conclusions: Our results support that genetic susceptibility related to the hepcidin-regulating gene pathway is associated with PDAC risk and suggest a potential role of iron metabolism in pancreatic carcinogenesis. Further studies are needed to evaluate effect modification by intake of iron-rich foods on this association.

Original languageEnglish (US)
Pages (from-to)1408-1417
Number of pages10
JournalAmerican Journal of Clinical Nutrition
Issue number4
StatePublished - Oct 1 2021


  • epidemiology
  • genetic susceptibility
  • hepcidin
  • iron metabolism pathway
  • pancreatic cancer

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Nutrition and Dietetics


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