Abstract

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.

Authors	Julián-Serrano, Sachelly; Yuan, Fangcheng; Wheeler, William; Benyamin, Beben; Machiela, Mitchell J; Arslan, Alan A; Beane-Freeman, Laura E; Bracci, Paige M; Duell, Eric J; Du, Mengmeng; Gallinger, Steven; Giles, Graham G; Goodman, Phyllis J; Kooperberg, Charles; Marchand, Loic Le; Neale, Rachel E; Shu, Xiao-Ou; Van Den Eeden, Stephen K; Visvanathan, Kala; Zheng, Wei; Albanes, Demetrius; Andreotti, Gabriella; Ardanaz, Eva; Babic, Ana; Berndt, Sonja I; Brais, Lauren K; Brennan, Paul; Bueno-de-Mesquita, Bas; Buring, Julie E; Chanock, Stephen J; Childs, Erica J; Chung, Charles C; Fabiánová, Eleonora; Foretová, Lenka; Fuchs, Charles S; Gaziano, J Michael; Gentiluomo, Manuel; Giovannucci, Edward L; Goggins, Michael G; Hackert, Thilo; Hartge, Patricia; Hassan, Manal M; Holcátová, Ivana; Holly, Elizabeth A; Hung, Rayjean I; Janout, Vladimir; Kurtz, Robert C; Lee, I-Min; Malats, Núria; McKean, David; Milne, Roger L; Newton, Christina C; Oberg, Ann L; Perdomo, Sandra; Peters, Ulrike; Porta, Miquel; Rothman, Nathaniel; Schulze, Matthias B; Sesso, Howard D; Silverman, Debra T; Thompson, Ian M; Wactawski-Wende, Jean; Weiderpass, Elisabete; Wenstzensen, Nicolas; White, Emily; Wilkens, Lynne R; Yu, Herbert; Zeleniuch-Jacquotte, Anne; Zhong, Jun; Kraft, Peter; Li, Dounghui; Campbell, Peter T; Petersen, Gloria M; Wolpin, Brian M; Risch, Harvey A; Amundadottir, Laufey T; Klein, Alison P; Yu, Kai; Stolzenberg-Solomon, Rachael Z
Journal	The American journal of clinical nutrition
Pages	1408-1417
Volume	114
Date	1/01/2021
Grant ID
Funding Body
URL	http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1093/ajcn/nqab217