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

Adenocarcinoma / metabolism Aged Case-Control Studies Female Gene Expression Regulation, Neoplastic / physiology Genotype Hepcidins / genetics Humans Iron / metabolism Linkage Disequilibrium Male Middle Aged Pancreatic Neoplasms / metabolism Polymorphism, Single Nucleotide
epidemiology genetic susceptibility hepcidin iron metabolism pathway pancreatic cancer

Journal

The American journal of clinical nutrition
ISSN: 1938-3207
Titre abrégé: Am J Clin Nutr
Pays: United States
ID NLM: 0376027

Informations de publication

Date de publication:
04 10 2021
Historique:
received: 14 01 2021
accepted: 08 06 2021
pubmed: 15 7 2021
medline: 26 10 2021
entrez: 14 7 2021
Statut: ppublish

Résumé

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.

Sections du résumé

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.

Identifiants

DOI: 10.1093/ajcn/nqab217 PMID: 34258619 PMC: PMC8488877
pubmed: 34258619
pii: S0002-9165(22)00469-5
doi: 10.1093/ajcn/nqab217
pmc: PMC8488877
doi:

Substances chimiques

Hepcidins 0
Iron E1UOL152H7

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

1408-1417

Subventions

Organisme : NCI NIH HHS
ID : U01 CA182883
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA062924
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL034595
Pays : United States
Organisme : Pancreatic Cancer Cohort II
ID : CA098380
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : MSKCC
ID : RO1CA102765
Organisme : Memorial Sloan Kettering Cancer Center
ID : P30CA008748
Organisme : NHLBI NIH HHS
ID : HHSN268201600018C
Pays : United States
Organisme : Hale Center for Pancreatic Cancer Research
ID : U01CA21017
Organisme : NCI NIH HHS
ID : R01 CA098380
Pays : United States
Organisme : NCI NIH HHS
ID : UM1 CA182883
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA247283
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201600001C
Pays : United States
Organisme : NIH HHS
ID : RO1CA154823
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201600003C
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA102765
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA182934
Pays : United States
Organisme : NCI NIH HHS
ID : UG1 CA189974
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201600002C
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA102701
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA015083
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201600004C
Pays : United States
Organisme : NCI NIH HHS
ID : U01CA164973
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA154823
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA049449
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA182913
Pays : United States
Organisme : NCI NIH HHS
ID : R03 CA123546
Pays : United States
Organisme : California Department of Public Health
ID : HSN261201000140C

Informations de copyright

Published by Oxford University Press on behalf of the American Society for Nutrition 2021.

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Auteurs

Sachelly Julián-Serrano (S)

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
ORCID: 0000-0002-8912-8232

Fangcheng Yuan (F)

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

William Wheeler (W)

Information Management Services, Silver Spring, MD, USA.

Beben Benyamin (B)

Australian Centre for Precision Health, Allied Health and Human Performance, University of South Australia, Adelaide, Australia.
South Australian Health and Medical Research Institute, Adelaide, Australia.

Mitchell J Machiela (MJ)

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

Alan A Arslan (AA)

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

Laura E Beane-Freeman (LE)

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

Paige M Bracci (PM)

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

Eric J Duell (EJ)

Unit of Biomarkers and Susceptibility, Oncology Data Analytics Program, Catalan Institute of Oncology, L'Hospitalet de Llobregat, Barcelona, Spain.
Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain.

Mengmeng Du (M)

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

Steven Gallinger (S)

Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada.

Graham G Giles (GG)

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.
Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Australia.
ORCID: 0000-0003-4946-9099

Phyllis J Goodman (PJ)

SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Charles Kooperberg (C)

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

Loic Le Marchand (LL)

Department of Epidemiology, University of Hawaii Cancer Center, Honolulu, HI, USA.

Rachel E Neale (RE)

Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
ORCID: 0000-0001-7162-0854

Xiao-Ou Shu (XO)

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

Stephen K Van Den Eeden (SK)

Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.
ORCID: 0000-0002-5599-8387

Kala Visvanathan (K)

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
ORCID: 0000-0002-0582-8005

Wei Zheng (W)

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

Demetrius Albanes (D)

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
ORCID: 0000-0001-8330-4293

Gabriella Andreotti (G)

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

Eva Ardanaz (E)

Navarra Public Health Institute, Pamplona, Spain.
IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain.

Ana Babic (A)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Sonja I Berndt (SI)

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

Lauren K Brais (LK)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Paul Brennan (P)

International Agency for Research on Cancer (IARC), Lyon, France.

Bas Bueno-de-Mesquita (B)

Department for Determinants of Chronic Diseases, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
ORCID: 0000-0002-1834-1829

Julie E Buring (JE)

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

Stephen J Chanock (SJ)

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

Erica J Childs (EJ)

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

Charles C Chung (CC)

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

Eleonora Fabiánová (E)

Specialized Institute of Hygiene and Epidemiology, Banska Bystrica, Slovakia.

Lenka Foretová (L)

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

Charles S Fuchs (CS)

Yale Cancer Center and Smilow Cancer Hospital, New Haven, CT, USA.
ORCID: 0000-0003-1582-9842

J Michael Gaziano (JM)

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

Manuel Gentiluomo (M)

Department of Biology, University of Pisa, Italy.
Genomic Epidemiology Group, German Cancer Research Center, (DKFZ), Heidelberg, Germany.

Edward L Giovannucci (EL)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Michael G Goggins (MG)

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

Thilo Hackert (T)

Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany.
ORCID: 0000-0002-7012-1196

Patricia Hartge (P)

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

Manal M Hassan (MM)

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

Ivana Holcátová (I)

Institute of Public Health and Preventive Medicine, Second Faculty of Medicine, Charles University, Prague, Czech Republic.

Elizabeth A Holly (EA)

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

Rayjean I Hung (RI)

Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada.

Vladimir Janout (V)

Faculty of Health Sciences, University of Olomouc, Olomouc, Czech Republic.

Robert C Kurtz (RC)

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

I-Min Lee (IM)

Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Núria Malats (N)

Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.

David McKean (D)

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

Roger L Milne (RL)

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

Christina C Newton (CC)

Department of Population Science, American Cancer Society, Atlanta, GA, USA.

Ann L Oberg (AL)

Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN, USA.
ORCID: 0000-0003-2539-9807

Sandra Perdomo (S)

International Agency for Research on Cancer (IARC), Lyon, France.

Ulrike Peters (U)

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

Miquel Porta (M)

Hospital del Mar Institute of Medical Research (IMIM), Universitat Autònoma de Barcelona, Barcelona, Spain.
ORCID: 0000-0003-1684-7428

Nathaniel Rothman (N)

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

Matthias B Schulze (MB)

Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany.

Howard D Sesso (HD)

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

Debra T Silverman (DT)

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

Ian M Thompson (IM)

CHRISTUS Santa Rosa Hospital-Medical Center, San Antonio, TX, USA.

Jean Wactawski-Wende (J)

Department of Epidemiology and Environmental Health, University at Buffalo, Buffalo, NY, USA.
ORCID: 0000-0003-3096-9595

Elisabete Weiderpass (E)

Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
ORCID: 0000-0003-2237-0128

Nicolas Wenstzensen (N)

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
ORCID: 0000-0003-1251-0836

Emily White (E)

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

Lynne R Wilkens (LR)

Department of Epidemiology, University of Hawaii Cancer Center, Honolulu, HI, USA.

Herbert Yu (H)

Department of Epidemiology, University of Hawaii Cancer Center, Honolulu, HI, USA.

Anne Zeleniuch-Jacquotte (A)

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

Jun Zhong (J)

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

Peter Kraft (P)

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
ORCID: 0000-0002-4472-8103

Dounghui Li (D)

Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
ORCID: 0000-0002-7542-0662

Peter T Campbell (PT)

Department of Population Science, American Cancer Society, Atlanta, GA, USA.

Gloria M Petersen (GM)

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

Brian M Wolpin (BM)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Harvey A Risch (HA)

Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA.
ORCID: 0000-0001-5337-3941

Laufey T Amundadottir (LT)

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

Alison P Klein (AP)

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.
ORCID: 0000-0003-2737-8399

Kai Yu (K)

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

Rachael Z Stolzenberg-Solomon (RZ)

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
ORCID: 0000-0003-3698-7006

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Classifications MeSH

questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs épithéliales épidermoïdes et glandulaires › Carcinomes › Adénocarcinome › Hepcidin-regulating iron metabolism genes and...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › Hepcidin-regulating iron metabolism genes and...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études épidémiologiques › Études cas-témoins › Hepcidin-regulating iron metabolism genes and...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Régulation de l'expression des gènes tumoraux › Hepcidin-regulating iron metabolism genes and...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Hepcidin-regulating iron metabolism genes and...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Perforines › Peptides antimicrobiens cationiques › Hepcidines › Hepcidin-regulating iron metabolism genes and...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Hepcidin-regulating iron metabolism genes and...
questionsmedicales.fr › Produits chimiques inorganiques › Métaux › Métaux lourds › Fer › Hepcidin-regulating iron metabolism genes and...
questionsmedicales.fr › Phénomènes génétiques › Liaison génétique › Déséquilibre de liaison › Hepcidin-regulating iron metabolism genes and...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Adulte d'âge moyen › Hepcidin-regulating iron metabolism genes and...
questionsmedicales.fr › Maladies endocriniennes › Tumeurs des glandes endocrines › Tumeurs du pancréas › Hepcidin-regulating iron metabolism genes and...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Polymorphisme génétique › Polymorphisme de nucléotide simple › Hepcidin-regulating iron metabolism genes and...