Hepcidin-regulating iron metabolism genes and pancreatic ductal adenocarcinoma: a pathway analysis of genome-wide association studies-Reference-Cited by-同舟云学术

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

Published:2021-07-13 Issue:4 Volume:114 Page:1408-1417
ISSN:0002-9165
Container-title:The American Journal of Clinical Nutrition
language:en
Short-container-title:

Author:

Julián-Serrano Sachelly¹^ORCID,Yuan Fangcheng¹,Wheeler William²,Benyamin Beben³⁴,Machiela Mitchell J¹,Arslan Alan A⁵,Beane-Freeman Laura E¹,Bracci Paige M⁶,Duell Eric J⁷⁸⁹,Du Mengmeng¹⁰,Gallinger Steven¹¹,Giles Graham G¹²¹³¹⁴^ORCID,Goodman Phyllis J¹⁵,Kooperberg Charles¹⁶,Marchand Loic Le¹⁷,Neale Rachel E¹⁸^ORCID,Shu Xiao-Ou¹⁹,Van Den Eeden Stephen K²⁰^ORCID,Visvanathan Kala²¹^ORCID,Zheng Wei¹⁹,Albanes Demetrius¹^ORCID,Andreotti Gabriella¹,Ardanaz Eva²²²³²⁴,Babic Ana²⁵,Berndt Sonja I¹,Brais Lauren K²⁵,Brennan Paul²⁶,Bueno-de-Mesquita Bas²⁷^ORCID,Buring Julie E²⁸,Chanock Stephen J¹,Childs Erica J²⁹,Chung Charles C¹,Fabiánová Eleonora³⁰,Foretová Lenka³¹,Fuchs Charles S³²^ORCID,Gaziano J Michael³³,Gentiluomo Manuel³⁴³⁵,Giovannucci Edward L²⁵,Goggins Michael G³⁶,Hackert Thilo³⁷^ORCID,Hartge Patricia¹,Hassan Manal M³⁸,Holcátová Ivana³⁹,Holly Elizabeth A⁶,Hung Rayjean I¹¹,Janout Vladimir⁴⁰,Kurtz Robert C⁴¹,Lee I-Min²⁸⁴²,Malats Núria⁴³,McKean David²⁹,Milne Roger L¹²¹³¹⁴,Newton Christina C⁴⁴,Oberg Ann L⁴⁵^ORCID,Perdomo Sandra²⁶,Peters Ulrike¹⁶,Porta Miquel⁴⁶^ORCID,Rothman Nathaniel¹,Schulze Matthias B⁴⁷⁴⁸,Sesso Howard D²⁸,Silverman Debra T¹,Thompson Ian M⁴⁹,Wactawski-Wende Jean⁵⁰^ORCID,Weiderpass Elisabete¹⁶^ORCID,Wenstzensen Nicolas¹^ORCID,White Emily¹⁶,Wilkens Lynne R¹⁷,Yu Herbert¹⁷,Zeleniuch-Jacquotte Anne⁵¹,Zhong Jun¹,Kraft Peter⁴²⁵²^ORCID,Li Dounghui⁵³^ORCID,Campbell Peter T⁴⁴,Petersen Gloria M⁴⁵,Wolpin Brian M²⁵,Risch Harvey A⁵⁴^ORCID,Amundadottir Laufey T¹,Klein Alison P²⁹³⁶^ORCID,Yu Kai¹,Stolzenberg-Solomon Rachael Z¹^ORCID

Affiliation:

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

2. Information Management Services, Silver Spring, MD, USA

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

4. South Australian Health and Medical Research Institute, Adelaide, Australia

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

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

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

8. Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain

9. Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain

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

11. Lunenfeld–Tanenbaum Research Institute, Sinai Health System, Toronto, Canada

12. Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Australia

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

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

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

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

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

18. Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia

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

20. Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA

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

22. Navarra Public Health Institute, Pamplona, Spain

23. IdiSNA, Navarra Institute for Health Research, Pamplona, Spain

24. CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain

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

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

27. Department for Determinants of Chronic Diseases, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands

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

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

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

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

32. Yale Cancer Center and Smilow Cancer Hospital, New Haven, CT, USA

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

34. Department of Biology, University of Pisa, Italy

35. Genomic Epidemiology Group, German Cancer Research Center, (DKFZ), Heidelberg, Germany

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

37. Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany

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

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

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

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

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

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

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

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

46. Hospital del Mar Institute of Medical Research (IMIM), Universitat Autònoma de Barcelona, Barcelona, Spain

47. Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany

48. Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany

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

50. Department of Epidemiology and Environmental Health, University at Buffalo, Buffalo, NY, USA

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

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

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

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

Abstract

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.

Funder

Division of Cancer Epidemiology and Genetics, National Cancer Institute

National Institutes of Health

International Agency for Research on Cancer

Ministry of Health of the Czech Republic

Johns Hopkins University

Lustgarten Foundation

Mayo Clinic SPORE

Pancreatic Cancer Cohort II

NCI

Memorial Sloan Kettering Cancer Center

Geoffrey Beene Foundation