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

Sachelly Julián-Serrano; Fangcheng Yuan; William Wheeler; Beben Benyamin; Mitchell J. Machiela; Alan A. Arslan; Laura E. Beane-Freeman; Paige M. Bracci; Eric J. Duell; Mengmeng Du; Steven Gallinger; Graham G. Giles; Phyllis J. Goodman; Charles Kooperberg; Loic Le Marchand; Rachel E. Neale; Xiao Ou Shu; Stephen K. Van Den Eeden; Kala Visvanathan; Wei Zheng; Demetrius Albanes; Gabriella Andreotti; Eva Ardanaz; Ana Babic; Sonja I. Berndt; Lauren K. Brais; Paul Brennan; Bas Bueno-De-Mesquita; Julie E. Buring; Stephen J. Chanock; Erica J. Childs; Charles C. Chung; Eleonora Fabiánová; Lenka Foretová; Charles S. Fuchs; J. Michael Gaziano; Manuel Gentiluomo; Edward L. Giovannucci; Michael G. Goggins; Thilo Hackert; Patricia Hartge; Manal M. Hassan; Ivana Holcátová; Elizabeth A. Holly; Rayjean I. Hung; Vladimir Janout; Robert C. Kurtz; I. Min Lee; Núria Malats; David McKean; Roger L. Milne; Christina C. Newton; Ann L. Oberg; Sandra Perdomo; Ulrike Peters; Miquel Porta; Nathaniel Rothman; Matthias B. Schulze; Howard D. Sesso; Debra T. Silverman; Ian M. Thompson; Jean Wactawski-Wende; Elisabete Weiderpass; Nicolas Wenstzensen; Emily White; Lynne R. Wilkens; Herbert Yu; Anne Zeleniuch-Jacquotte; Jun Zhong; Peter Kraft; Dounghui Li; Peter T. Campbell; Gloria M. Petersen; Brian M. Wolpin; Harvey A. Risch; Laufey T. Amundadottir; Alison P. Klein; Kai Yu; Rachael Z. Stolzenberg-Solomon

doi:10.1093/ajcn/nqab217

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

Sachelly Julián-Serrano, Fangcheng Yuan, William Wheeler, Beben Benyamin, Mitchell J. Machiela, Alan A. Arslan, Laura E. Beane-Freeman, Paige M. Bracci, Eric J. Duell, Mengmeng Du, Steven Gallinger, Graham G. Giles, Phyllis J. Goodman, Charles Kooperberg, Loic Le Marchand, Rachel E. Neale, Xiao Ou Shu, Stephen K. Van Den Eeden, Kala Visvanathan, Wei ZhengDemetrius Albanes, Gabriella Andreotti, Eva Ardanaz, Ana Babic, Sonja I. Berndt, Lauren K. Brais, Paul Brennan, Bas Bueno-De-Mesquita, Julie E. Buring, Stephen J. Chanock, Erica J. Childs, Charles C. Chung, Eleonora Fabiánová, Lenka Foretová, Charles S. Fuchs, J. Michael Gaziano, Manuel Gentiluomo, Edward L. Giovannucci, Michael G. Goggins, Thilo Hackert, Patricia Hartge, Manal M. Hassan, Ivana Holcátová, Elizabeth A. Holly, Rayjean I. Hung, Vladimir Janout, Robert C. Kurtz, I. Min Lee, Núria Malats, David McKean, Roger L. Milne, Christina C. Newton, Ann L. Oberg, Sandra Perdomo, Ulrike Peters, Miquel Porta, Nathaniel Rothman, Matthias B. Schulze, Howard D. Sesso, Debra T. Silverman, Ian M. Thompson, Jean Wactawski-Wende, Elisabete Weiderpass, Nicolas Wenstzensen, Emily White, Lynne R. Wilkens, Herbert Yu, Anne Zeleniuch-Jacquotte, Jun Zhong, Peter Kraft, Dounghui Li, Peter T. Campbell, Gloria M. Petersen, Brian M. Wolpin, Harvey A. Risch, Laufey T. Amundadottir, Alison P. Klein, Kai Yu, Rachael Z. Stolzenberg-Solomon

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Pages (from-to)	1408-1417
Number of pages	10
Journal	American Journal of Clinical Nutrition
Volume	114
Issue number	4
DOIs	https://doi.org/10.1093/ajcn/nqab217
State	Published - Oct 1 2021

Keywords

epidemiology
genetic susceptibility
hepcidin
iron metabolism pathway
pancreatic cancer

ASJC Scopus subject areas

Medicine (miscellaneous)
Nutrition and Dietetics

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10.1093/ajcn/nqab217

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Julián-Serrano, S., Yuan, F., Wheeler, W., Benyamin, B., Machiela, M. J., Arslan, A. A., Beane-Freeman, L. E., Bracci, P. M., Duell, E. J., Du, M., Gallinger, S., Giles, G. G., Goodman, P. J., Kooperberg, C., Marchand, L. L., Neale, R. E., Shu, X. O., Van Den Eeden, S. K., Visvanathan, K., ... Stolzenberg-Solomon, R. Z. (2021). Hepcidin-regulating iron metabolism genes and pancreatic ductal adenocarcinoma: A pathway analysis of genome-wide association studies. American Journal of Clinical Nutrition, 114(4), 1408-1417. https://doi.org/10.1093/ajcn/nqab217

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, 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 2021, 'Hepcidin-regulating iron metabolism genes and pancreatic ductal adenocarcinoma: A pathway analysis of genome-wide association studies', American Journal of Clinical Nutrition, vol. 114, no. 4, pp. 1408-1417. https://doi.org/10.1093/ajcn/nqab217

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title = "Hepcidin-regulating iron metabolism genes and pancreatic ductal adenocarcinoma: A pathway analysis of genome-wide association studies",

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.",

keywords = "epidemiology, genetic susceptibility, hepcidin, iron metabolism pathway, pancreatic cancer",

author = "Sachelly Juli{\'a}n-Serrano and Fangcheng Yuan and William Wheeler and Beben Benyamin and Machiela, {Mitchell J.} and Arslan, {Alan A.} and Beane-Freeman, {Laura E.} and Bracci, {Paige M.} and Duell, {Eric J.} and Mengmeng Du and Steven Gallinger and Giles, {Graham G.} and Goodman, {Phyllis J.} and Charles Kooperberg and Marchand, {Loic Le} and Neale, {Rachel E.} and Shu, {Xiao Ou} and {Van Den Eeden}, {Stephen K.} and Kala Visvanathan and Wei Zheng and Demetrius Albanes and Gabriella Andreotti and Eva Ardanaz and Ana Babic and Berndt, {Sonja I.} and Brais, {Lauren K.} and Paul Brennan and Bas Bueno-De-Mesquita and Buring, {Julie E.} and Chanock, {Stephen J.} and Childs, {Erica J.} and Chung, {Charles C.} and Eleonora Fabi{\'a}nov{\'a} and Lenka Foretov{\'a} and Fuchs, {Charles S.} and Gaziano, {J. Michael} and Manuel Gentiluomo and Giovannucci, {Edward L.} and Goggins, {Michael G.} and Thilo Hackert and Patricia Hartge and Hassan, {Manal M.} and Ivana Holc{\'a}tov{\'a} and Holly, {Elizabeth A.} and Hung, {Rayjean I.} and Vladimir Janout and Kurtz, {Robert C.} and Lee, {I. Min} and N{\'u}ria Malats and David McKean and Milne, {Roger L.} and Newton, {Christina C.} and Oberg, {Ann L.} and Sandra Perdomo and Ulrike Peters and Miquel Porta and Nathaniel Rothman and Schulze, {Matthias B.} and Sesso, {Howard D.} and Silverman, {Debra T.} and Thompson, {Ian M.} and Jean Wactawski-Wende and Elisabete Weiderpass and Nicolas Wenstzensen and Emily White and Wilkens, {Lynne R.} and Herbert Yu and Anne Zeleniuch-Jacquotte and Jun Zhong and Peter Kraft and Dounghui Li and Campbell, {Peter T.} and Petersen, {Gloria M.} and Wolpin, {Brian M.} and Risch, {Harvey A.} and Amundadottir, {Laufey T.} and Klein, {Alison P.} and Kai Yu and Stolzenberg-Solomon, {Rachael Z.}",

note = "Publisher Copyright: {\textcopyright} 2021 Published by Oxford University Press on behalf of the American Society for Nutrition 2021.",

year = "2021",

month = oct,

day = "1",

doi = "10.1093/ajcn/nqab217",

language = "English (US)",

volume = "114",

pages = "1408--1417",

journal = "American Journal of Clinical Nutrition",

issn = "0002-9165",

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number = "4",

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TY - JOUR

T1 - Hepcidin-regulating iron metabolism genes and pancreatic ductal adenocarcinoma

T2 - A pathway analysis of genome-wide association studies

AU - Julián-Serrano, Sachelly

AU - Yuan, Fangcheng

AU - Wheeler, William

AU - Benyamin, Beben

AU - Machiela, Mitchell J.

AU - Arslan, Alan A.

AU - Beane-Freeman, Laura E.

AU - Bracci, Paige M.

AU - Duell, Eric J.

AU - Du, Mengmeng

AU - Gallinger, Steven

AU - Giles, Graham G.

AU - Goodman, Phyllis J.

AU - Kooperberg, Charles

AU - Marchand, Loic Le

AU - Neale, Rachel E.

AU - Shu, Xiao Ou

AU - Van Den Eeden, Stephen K.

AU - Visvanathan, Kala

AU - Zheng, Wei

AU - Albanes, Demetrius

AU - Andreotti, Gabriella

AU - Ardanaz, Eva

AU - Babic, Ana

AU - Berndt, Sonja I.

AU - Brais, Lauren K.

AU - Brennan, Paul

AU - Bueno-De-Mesquita, Bas

AU - Buring, Julie E.

AU - Chanock, Stephen J.

AU - Childs, Erica J.

AU - Chung, Charles C.

AU - Fabiánová, Eleonora

AU - Foretová, Lenka

AU - Fuchs, Charles S.

AU - Gaziano, J. Michael

AU - Gentiluomo, Manuel

AU - Giovannucci, Edward L.

AU - Goggins, Michael G.

AU - Hackert, Thilo

AU - Hartge, Patricia

AU - Hassan, Manal M.

AU - Holcátová, Ivana

AU - Holly, Elizabeth A.

AU - Hung, Rayjean I.

AU - Janout, Vladimir

AU - Kurtz, Robert C.

AU - Lee, I. Min

AU - Malats, Núria

AU - McKean, David

AU - Milne, Roger L.

AU - Newton, Christina C.

AU - Oberg, Ann L.

AU - Perdomo, Sandra

AU - Peters, Ulrike

AU - Porta, Miquel

AU - Rothman, Nathaniel

AU - Schulze, Matthias B.

AU - Sesso, Howard D.

AU - Silverman, Debra T.

AU - Thompson, Ian M.

AU - Wactawski-Wende, Jean

AU - Weiderpass, Elisabete

AU - Wenstzensen, Nicolas

AU - White, Emily

AU - Wilkens, Lynne R.

AU - Yu, Herbert

AU - Zeleniuch-Jacquotte, Anne

AU - Zhong, Jun

AU - Kraft, Peter

AU - Li, Dounghui

AU - Campbell, Peter T.

AU - Petersen, Gloria M.

AU - Wolpin, Brian M.

AU - Risch, Harvey A.

AU - Amundadottir, Laufey T.

AU - Klein, Alison P.

AU - Yu, Kai

AU - Stolzenberg-Solomon, Rachael Z.

PY - 2021/10/1

Y1 - 2021/10/1

N2 - 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.

AB - 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.

KW - epidemiology

KW - genetic susceptibility

KW - hepcidin

KW - iron metabolism pathway

KW - pancreatic cancer

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UR - http://www.scopus.com/inward/citedby.url?scp=85117182037&partnerID=8YFLogxK

U2 - 10.1093/ajcn/nqab217

DO - 10.1093/ajcn/nqab217

M3 - Article

C2 - 34258619

AN - SCOPUS:85117182037

SN - 0002-9165

VL - 114

SP - 1408

EP - 1417

JO - American Journal of Clinical Nutrition

JF - American Journal of Clinical Nutrition

IS - 4

ER -

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

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