Dataset Information

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.

SUBMITTER: Julian-Serrano S

PROVIDER: S-EPMC8488877 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Publications

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

Julián-Serrano Sachelly S Yuan Fangcheng F Wheeler William W Benyamin Beben B Machiela Mitchell J MJ Arslan Alan A AA Beane-Freeman Laura E LE Bracci Paige M PM Duell Eric J EJ Du Mengmeng M Gallinger Steven S Giles Graham G GG Goodman Phyllis J PJ Kooperberg Charles C Marchand Loic Le LL Neale Rachel E RE Shu Xiao-Ou XO Van Den Eeden Stephen K SK Visvanathan Kala K Zheng Wei W Albanes Demetrius D Andreotti Gabriella G Ardanaz Eva E Babic Ana A Berndt Sonja I SI Brais Lauren K LK Brennan Paul P Bueno-de-Mesquita Bas B Buring Julie E JE Chanock Stephen J SJ Childs Erica J EJ Chung Charles C CC Fabiánová Eleonora E Foretová Lenka L Fuchs Charles S CS Gaziano J Michael JM Gentiluomo Manuel M Giovannucci Edward L EL Goggins Michael G MG Hackert Thilo T Hartge Patricia P Hassan Manal M MM Holcátová Ivana I Holly Elizabeth A EA Hung Rayjean I RI Janout Vladimir V Kurtz Robert C RC Lee I-Min IM Malats Núria N McKean David D Milne Roger L RL Newton Christina C CC Oberg Ann L AL Perdomo Sandra S Peters Ulrike U Porta Miquel M Rothman Nathaniel N Schulze Matthias B MB Sesso Howard D HD Silverman Debra T DT Thompson Ian M IM Wactawski-Wende Jean J Weiderpass Elisabete E Wenstzensen Nicolas N White Emily E Wilkens Lynne R LR Yu Herbert H Zeleniuch-Jacquotte Anne A Zhong Jun J Kraft Peter P Li Dounghui D Campbell Peter T PT Petersen Gloria M GM Wolpin Brian M BM Risch Harvey A HA Amundadottir Laufey T LT Klein Alison P AP Yu Kai K Stolzenberg-Solomon Rachael Z RZ

The American journal of clinical nutrition 20211001 4

<h4>Background</h4>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.<h4>Objectives</h4>The objective of this study was to determine whether common genetic variation in the hepcidin-regulating iron metabolism pathway is associated with PDAC.<h4>Methods</ ...[more]

PMID: 34258619

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Project description:Anemia and iron deficiency (ID) are common complications in patients with pancreatic ductal adenocarcinoma (PDAC), but their underlying causes remain unclear. This study investigated the incidence and characteristics of anemia and micronutrient deficiencies in PDAC patients before initiating chemotherapy. A total of 103 PDAC patients were included, comprising 67 in the palliative and 36 in the adjuvant groups. The overall incidence of anemia was 42.7% (n = 44), with comparable rates in both groups. Normocytic and normochromic anemia were predominant, with mild and moderate cases observed in 32% and 10.7% of the cohort, respectively. ID was evident in 51.4% of patients, with absolute ID more frequent in the adjuvant than in the palliative group (19.4% vs. 13.4%). Functional ID occurred more often in the palliative than in the adjuvant group (41.8% vs. 25%). Vitamin B12 and folate deficiency occurred in <5% (n = 5) of patients. Furthermore, 8.7% (n = 9) of patients had chronic kidney disease and anemia. To elucidate mechanisms of iron deficiency, the study explored the expression of iron regulators (hepcidin (HEP), ferroportin (FPN), and ZIP14 protein) and mitochondrial mass in PDAC tissue with immunohistochemical (IHC) staining and Perl's Prussian blue to detect iron deposits on available tumor samples (n = 56). ZIP14 expression was significantly higher in less advanced tumors (p = 0.01) and correlated with mitochondrial mass (p < 0.001), potentially indicating its role in local iron homeostasis. However, no significant impact of tissue iron regulators on patient survival was observed. Perl's Prussian blue staining revealed iron deposits within macrophages, but not in pancreatic duct cells. Furthermore, the GEPIA database was used to compare mRNA expression of iron regulators (HEP, FPN, and ZIP14) and other genes encoding iron transport and storage, including Transferrin Receptor Protein 1 (TfR1) and both ferritin chain subunits (FTH and FTL), in PDAC and normal pancreatic samples. FPN, TfR1, FTH, and FTL showed higher expression in tumor tissues, indicating increased iron usage by cancer. ZIP14 expression was higher in the pancreas than in PDAC and was correlated with FPN expression. The study highlights the importance of baseline iron status assessment in managing PDAC patients due to the high incidence of anemia and iron deficiency. Furthermore, ZIP14, in addition to HEP and FPN, may play a crucial role in local iron homeostasis in PDAC patients, providing valuable insights into the underlying mechanisms of iron dysregulation.

Dataset Information

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

Background

Objectives

Methods

Results

Conclusions

Publications

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

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