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

About this Publication
Title
Hepcidin-regulating iron metabolism genes and pancreatic ductal adenocarcinoma: a pathway analysis of genome-wide association studies.
Pubmed ID
34258619 (View this publication on the PubMed website)
Digital Object Identifier
Publication
Am J Clin Nutr. 2021 Oct 4; Volume 114 (Issue 4): Pages 1408-1417
Authors
Julián-Serrano S, Yuan F, Wheeler W, Benyamin B, Machiela MJ, Arslan AA, Beane-Freeman LE, Bracci PM, Duell EJ, Du M, Gallinger S, Giles GG, Goodman PJ, Kooperberg C, Marchand LL, Neale RE, Shu XO, Van Den Eeden SK, Visvanathan K, Zheng W, ...show more Albanes D, Andreotti G, Ardanaz E, Babic A, Berndt SI, Brais LK, Brennan P, Bueno-de-Mesquita B, Buring JE, Chanock SJ, Childs EJ, Chung CC, Fabiánová E, Foretová L, Fuchs CS, Gaziano JM, Gentiluomo M, Giovannucci EL, Goggins MG, Hackert T, Hartge P, Hassan MM, Holcátová I, Holly EA, Hung RI, Janout V, Kurtz RC, Lee IM, Malats N, McKean D, Milne RL, Newton CC, Oberg AL, Perdomo S, Peters U, Porta M, Rothman N, Schulze MB, Sesso HD, Silverman DT, Thompson IM, Wactawski-Wende J, Weiderpass E, Wenstzensen N, White E, Wilkens LR, Yu H, Zeleniuch-Jacquotte A, Zhong J, Kraft P, Li D, Campbell PT, Petersen GM, Wolpin BM, Risch HA, Amundadottir LT, Klein AP, Yu K, Stolzenberg-Solomon RZ
Affiliations
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
  • Information Management Services, Silver Spring, MD, USA.
  • Australian Centre for Precision Health, Allied Health and Human Performance, University of South Australia, Adelaide, Australia.
  • Department of Obstetrics and Gynecology, New York University School of Medicine, New York, NY, USA.
  • Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
  • Unit of Biomarkers and Susceptibility, Oncology Data Analytics Program, Catalan Institute of Oncology, L'Hospitalet de Llobregat, Barcelona, Spain.
  • Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada.
  • Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Australia.
  • SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
...show more
  • Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • Department of Epidemiology, University of Hawaii Cancer Center, Honolulu, HI, USA.
  • Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
  • Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
  • Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.
  • Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
  • Navarra Public Health Institute, Pamplona, Spain.
  • Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • International Agency for Research on Cancer (IARC), Lyon, France.
  • Department for Determinants of Chronic Diseases, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
  • Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
  • Specialized Institute of Hygiene and Epidemiology, Banska Bystrica, Slovakia.
  • Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
  • Yale Cancer Center and Smilow Cancer Hospital, New Haven, CT, USA.
  • Division of Aging, Brigham and Women's Hospital, Boston, MA, USA.
  • Department of Biology, University of Pisa, Italy.
  • Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
  • Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany.
  • Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Institute of Public Health and Preventive Medicine, Second Faculty of Medicine, Charles University, Prague, Czech Republic.
  • Faculty of Health Sciences, University of Olomouc, Olomouc, Czech Republic.
  • Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
  • Department of Population Science, American Cancer Society, Atlanta, GA, USA.
  • Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN, USA.
  • Hospital del Mar Institute of Medical Research (IMIM), Universitat Autònoma de Barcelona, Barcelona, Spain.
  • Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
  • CHRISTUS Santa Rosa Hospital-Medical Center, San Antonio, TX, USA.
  • Department of Epidemiology and Environmental Health, University at Buffalo, Buffalo, NY, USA.
  • Department of Population Health and Perlmutter Cancer Center, New York University School of Medicine, New York, NY, USA.
  • Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
  • Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA.
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.

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