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

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.The...

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Main Authors: Julián-Serrano, Sachelly (Author) , Yuan, Fangcheng (Author) , Wheeler, William (Author) , Benyamin, Beben (Author) , Machiela, Mitchell J (Author) , Arslan, Alan A (Author) , Beane-Freeman, Laura E (Author) , Bracci, Paige M (Author) , Duell, Eric J (Author) , Du, Mengmeng (Author) , Gallinger, Steven (Author) , Giles, Graham G (Author) , Goodman, Phyllis J (Author) , Kooperberg, Charles (Author) , Marchand, Loic Le (Author) , Neale, Rachel E (Author) , Shu, Xiao-Ou (Author) , Van Den Eeden, Stephen K (Author) , Visvanathan, Kala (Author) , Zheng, Wei (Author) , Albanes, Demetrius (Author) , Andreotti, Gabriella (Author) , Ardanaz, Eva (Author) , Babic, Ana (Author) , Berndt, Sonja I (Author) , Brais, Lauren K (Author) , Brennan, Paul (Author) , Bueno-de-Mesquita, Bas (Author) , Buring, Julie E (Author) , Chanock, Stephen J (Author) , Childs, Erica J (Author) , Chung, Charles C (Author) , Fabiánová, Eleonora (Author) , Foretová, Lenka (Author) , Fuchs, Charles S (Author) , Gaziano, J Michael (Author) , Gentiluomo, Manuel (Author) , Giovannucci, Edward L (Author) , Goggins, Michael G (Author) , Hackert, Thilo (Author) , Hartge, Patricia (Author) , Hassan, Manal M (Author) , Holcátová, Ivana (Author) , Holly, Elizabeth A (Author) , Hung, Rayjean I (Author) , Janout, Vladimir (Author) , Kurtz, Robert C (Author) , Lee, I-Min (Author) , Malats, Núria (Author) , McKean, David (Author) , Milne, Roger L (Author) , Newton, Christina C (Author) , Oberg, Ann L (Author) , Perdomo, Sandra (Author) , Peters, Ulrike (Author) , Porta, Miquel (Author) , Rothman, Nathaniel (Author) , Schulze, Matthias B (Author) , Sesso, Howard D (Author) , Silverman, Debra T (Author) , Thompson, Ian M (Author) , Wactawski-Wende, Jean (Author) , Weiderpass, Elisabete (Author) , Wenstzensen, Nicolas (Author) , White, Emily (Author) , Wilkens, Lynne R (Author) , Yu, Herbert (Author) , Zeleniuch-Jacquotte, Anne (Author) , Zhong, Jun (Author) , Kraft, Peter (Author) , Li, Dounghui (Author) , Campbell, Peter T (Author) , Petersen, Gloria M (Author) , Wolpin, Brian M (Author) , Risch, Harvey A (Author) , Amundadottir, Laufey T (Author) , Klein, Alison P (Author) , Yu, Kai (Author) , Stolzenberg-Solomon, Rachael Z (Author)
Format: Article (Journal)
Language:English
Published: 13 July 2021
In: The American journal of clinical nutrition
Year: 2021, Volume: 114, Issue: 4, Pages: 1408-1417
ISSN:1938-3207
DOI:10.1093/ajcn/nqab217
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1093/ajcn/nqab217
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Author Notes: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 Zheng, Demetrius 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, and Rachael Z Stolzenberg-Solomon
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Summary: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.The objective of this study was to determine whether common genetic variation in the hepcidin-regulating iron metabolism pathway is associated with PDAC.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.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.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.
Item Description:Gesehen am 17.01.2022
Physical Description:Online Resource
ISSN:1938-3207
DOI:10.1093/ajcn/nqab217

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