Journal
AMERICAN JOURNAL OF CLINICAL NUTRITION
Volume 114, Issue 4, Pages 1408-1417Publisher
ELSEVIER SCIENCE INC
DOI: 10.1093/ajcn/nqab217
Keywords
hepcidin; iron metabolism pathway; pancreatic cancer; genetic susceptibility; epidemiology
Categories
Funding
- Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health
- NCI-NIH [R03CA123546-02, 5R01CA098870]
- Ministry of Health of the Czech Republic [NR 9029-4/2006, NR9422-3, MH CZ-DRO-MMCI 00209805]
- NCI [P50CA062924, R01CA97075, R01CA154382, U01CA247283, U01CA164973, UM1CA167552, UM1 CA186107, P01CA87969, R01CA49449, U01CA21017]
- Lustgarten Foundation
- Susan Wojcicki and Dennis Troper
- Sol Goldman Pancreas Cancer Research Center
- Mayo Clinic SPORE in Pancreatic Cancer [P50 CA102701]
- NIH-NCI [5R01CA098870, R01CA098380, R01CA1009767, R01CA109767-S1, R0CA059706]
- Geoffrey Beene Foundation
- Arnold and Arlene Goldstein Family Foundation
- Society of MSKCC
- Kaiser Permanente and Group Health Cooperative [RO1CA102765]
- National Health and Medical Research Council of Australia (NHMRC) [442302]
- NHMRC Senior Research Fellowship [1060183]
- Joan Rombauer Pancreatic Cancer Fund
- California Department of Public Health [HSN261201000140C]
- CDC's National Program of Cancer Registries [U58DP003862-01]
- Czech Science Foundation [P301/12/1734, IGA NT 13 263]
- Baden-Wurttemberg State Ministry of Research, Science and Arts
- Heidelberger EPZ-Pancobank [01GS08114]
- BMBH [01EY1101]
- 5 x 1000 voluntary contribution of the Italian Government
- Italian Ministry of Health [RC1203GA57, RC1303GA53, RC1303GA54, RC1303GA50]
- Italian Association for Research on Cancer [AIRC 12182]
- Italian Ministry of Research [FIRB-RBAP10AHJB]
- Italian FIMP-Ministry of Health [12 CUP_J33G13000210001]
- National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, UK
- American Cancer Society
- VicHealth
- Cancer Council Victoria
- Australian National Health and Medical Research Council [209057, 396414, 1074383]
- NIH [R01CA098661, UM1CA182934, P30CA016087, P30ES000260, CA097193, CA34944, CA40360, HL26490, HL34595, UM1CA173640, UM1CA182910, U10CA37429, UM1CA182883]
- Instituto de Salud Carlos III-FEDER, Spain: Fondo de Investigaciones Sanitarias [FIS: PI13/00082, PI15/01573]
- Red Tematica de Investigacion Cooperativa en Cancer, Spain [RD12/0036/0050]
- European Cooperation in Science and Technology [COST Action BM1204: EU_Pancreas]
- Ministerio de Ciencia y Tecnologia [CICYT SAF 2000-0097]
- Fondo de Investigacion Sanitaria [95/0017]
- Madrid, Spain
- Generalitat de Catalunya (CIRIT -SGR)
- Red tematica de investigacion cooperativa de centros en Cancer [C03/10]
- Red tematica de investigacion cooperativa de centros en Epidemiologia y salud publica [C03/09]
- CIBER de Epidemiologia (CIBERESP), Madrid, Spain
- Hale Center for Pancreatic Cancer Research
- US Department of Defense [CA130288]
- Pancreatic Cancer Action Network
- Noble Effort Fund
- Peter R. Leavitt Family Fund
- Wexler Family Fund
- Instituto de Salud Carlos III
- FEDER funds-a way to build Europe [FIS: PI15/00659, PI18-00192]
- Fundacio La Marato de TV3 [20192-30]
- Agency for Management of University and Research Grants (AGAUR) of the Catalan Government [2017SGR723]
- Spanish Association Against Cancer Scientific Foundation
- NationalHeart, Lung, and Blood Institute, NIH, US Department of Health and Human Services [HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, HHSN268201600004C]
- NIH
- NCI
- National Human Genome Research Institute
- National Heart, Lung, and Blood Institute
- National Institute on Drug Abuse
- National Institute of Mental Health
- National Institute of Neurological Disorders and Stroke
- [CA098380]
- [P30CA008748]
- [RO1CA154823]
- National Health and Medical Research Council of Australia [1060183] Funding Source: NHMRC
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The study found that the hepcidin-regulating gene pathway is associated with the risk of pancreatic ductal adenocarcinoma, with HJV, TFR2, TFR1, BMP6 and HAMP genes contributing the most to the association.
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 transfenin 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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