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.

Australian Centre for Precision Health Allied Health and Human Performance University of South Australia Adelaide Australia

Cancer Epidemiology Division Cancer Council Victoria Melbourne Australia

Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health The University of Melbourne Melbourne Australia

CHRISTUS Santa Rosa Hospital Medical Center San Antonio TX USA

CIBER Epidemiología y Salud Pública Barcelona Spain

Colorectal Cancer Group ONCOBELL Program Bellvitge Biomedical Research Institute L'Hospitalet de Llobregat Barcelona Spain

Consortium for Biomedical Research in Epidemiology and Public Health Madrid Spain

Department for Determinants of Chronic Diseases National Institute for Public Health and the Environment Bilthoven The Netherlands

Department of Biology University of Pisa Italy

Department of Biostatistics Harvard T H Chan School of Public Health Boston MA USA

Department of Cancer Epidemiology and Genetics Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Chronic Disease Epidemiology Yale School of Public Health New Haven CT USA

Department of Epidemiology and Biostatistics Memorial Sloan Kettering Cancer Center New York NY USA

Department of Epidemiology and Biostatistics University of California San Francisco San Francisco CA USA

Department of Epidemiology and Environmental Health University at Buffalo Buffalo NY USA

Department of Epidemiology Harvard T H Chan School of Public Health Boston MA USA

Department of Epidemiology Johns Hopkins Bloomberg School of Public Health Baltimore MD USA

Department of Epidemiology University of Hawaii Cancer Center Honolulu HI USA

Department of Epidemiology University of Texas MD Anderson Cancer Center Houston TX USA

Department of Gastrointestinal Medical Oncology The University of Texas MD Anderson Cancer Center Houston TX USA

Department of General Visceral and Transplantation Surgery Heidelberg University Hospital Heidelberg Germany

Department of Health Sciences Research Mayo Clinic College of Medicine Rochester MN USA

Department of Medical Oncology Dana Farber Cancer Institute Boston MA USA

Department of Medicine Memorial Sloan Kettering Cancer Center New York NY USA

Department of Molecular Epidemiology German Institute of Human Nutrition Potsdam Rehbruecke Nuthetal Germany

Department of Obstetrics and Gynecology New York University School of Medicine New York NY USA

Department of Oncology The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore MD USA

Department of Pathology Sol Goldman Pancreatic Cancer Research Center Johns Hopkins School of Medicine Baltimore MD USA

Department of Population Health and Perlmutter Cancer Center New York University School of Medicine New York NY USA

Department of Population Science American Cancer Society Atlanta GA USA

Division of Aging Brigham and Women's Hospital Boston MA USA

Division of Cancer Epidemiology and Genetics National Cancer Institute Rockville MD USA

Division of Epidemiology Department of Medicine Vanderbilt Epidemiology Center Vanderbilt Ingram Cancer Center Vanderbilt University School of Medicine Nashville TN USA

Division of Preventive Medicine Brigham and Women's Hospital and Harvard Medical School Boston MA USA

Division of Public Health Sciences Fred Hutchinson Cancer Research Center Seattle WA USA

Division of Research Kaiser Permanente Northern California Oakland CA USA

Faculty of Health Sciences University of Olomouc Olomouc Czech Republic

Genetic and Molecular Epidemiology Group Spanish National Cancer Research Centre Madrid Spain

Genomic Epidemiology Group German Cancer Research Center Heidelberg Germany

Hospital del Mar Institute of Medical Research Universitat Autònoma de Barcelona Barcelona Spain

IdiSNA Navarra Institute for Health Research Pamplona Spain

Information Management Services Silver Spring MD USA

Institute of Nutritional Science University of Potsdam Nuthetal Germany

Institute of Public Health and Preventive Medicine 2nd Faculty of Medicine Charles University Prague Czech Republic

International Agency for Research on Cancer Lyon France

Lunenfeld Tanenbaum Research Institute Sinai Health System Toronto Canada

Navarra Public Health Institute Pamplona Spain

Population Health Department QIMR Berghofer Medical Research Institute Brisbane Australia

Precision Medicine School of Clinical Sciences at Monash Health Monash University Clayton Australia

South Australian Health and Medical Research Institute Adelaide Australia

Specialized Institute of Hygiene and Epidemiology Banska Bystrica Slovakia

SWOG Statistical Center Fred Hutchinson Cancer Research Center Seattle WA USA

Unit of Biomarkers and Susceptibility Oncology Data Analytics Program Catalan Institute of Oncology L'Hospitalet de Llobregat Barcelona Spain

Yale Cancer Center and Smilow Cancer Hospital New Haven CT USA

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