Novel loci and biomedical consequences of iron homoeostasis variation

Elias Allara; Steven Bell; Rebecca Smith; Spencer J Keene; Dipender Gill; Liam Gaziano; Deisy Morselli Gysi; Feiyi Wang; Vinicius Tragante; Amy Mason; Savita Karthikeyan; R Thomas Lumbers; Emmanuela Bonglack; Willem Ouwehand; David J Roberts; Joseph Dowsett; Sisse Rye Ostrowski; Margit Hørup Larsen; Henrik Ullum; Ole Birger Pedersen; Søren Brunak; Karina Banasik; Christian Erikstrup; Jonathan Mitchell; Christian Fuchsberger; Cristian Pattaro; Peter P Pramstaller; Domenico Girelli; Mikko Arvas; Jarkko Toivonen; Sophie Molnos; Annette Peters; Ozren Polasek; Igor Rudan; Caroline Hayward; Ciara McDonnell; Nicola Pirastu; James F Wilson; Katja van den Hurk; Franke Quee; Luigi Ferrucci; Stefania Bandinelli; Toshiko Tanaka; Giorgia Girotto; Maria Pina Concas; Alessandro Pecori; Niek Verweij; Pim van der Harst; Yordi J van de Vegte; Emanuele Di Angelantonio; DBDS Genomic Consortium

doi:10.1038/s42003-024-07115-3

Novel loci and biomedical consequences of iron homoeostasis variation

Elias Allara^*
, Steven Bell
, Rebecca Smith
, Spencer J Keene
, Dipender Gill
, Liam Gaziano
, Deisy Morselli Gysi
, Feiyi Wang
, Vinicius Tragante
, Amy Mason
, Savita Karthikeyan
, R Thomas Lumbers
, Emmanuela Bonglack
, Willem Ouwehand
, David J Roberts
, Joseph Dowsett
, Sisse Rye Ostrowski
, Margit Hørup Larsen
, Henrik Ullum
, Ole Birger Pedersen

Søren Brunak, Karina Banasik, Christian Erikstrup, Jonathan Mitchell, Christian Fuchsberger, Cristian Pattaro, Peter P Pramstaller, Domenico Girelli, Mikko Arvas, Jarkko Toivonen, Sophie Molnos, Annette Peters, Ozren Polasek, Igor Rudan, Caroline Hayward, Ciara McDonnell, Nicola Pirastu, James F Wilson, Katja van den Hurk, Franke Quee, Luigi Ferrucci, Stefania Bandinelli, Toshiko Tanaka, Giorgia Girotto, Maria Pina Concas, Alessandro Pecori, Niek Verweij, Pim van der Harst, Yordi J van de Vegte, Emanuele Di Angelantonio, DBDS Genomic Consortium

^*Corresponding author for this work

Clinical Immunology

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

Abstract

Iron homoeostasis is tightly regulated, with hepcidin and soluble transferrin receptor (sTfR) playing significant roles. However, the genetic determinants of these traits and the biomedical consequences of iron homoeostasis variation are unclear. In a meta-analysis of 12 cohorts involving 91,675 participants, we found 43 genomic loci associated with either hepcidin or sTfR concentration, of which 15 previously unreported. Mapping to putative genes indicated involvement in iron-trait expression, erythropoiesis, immune response and cellular trafficking. Mendelian randomisation of 292 disease outcomes in 1,492,717 participants revealed associations of iron-related loci and iron status with selected health outcomes across multiple domains. These associations were largely driven by HFE, which was associated with the largest iron variation. Our findings enhance understanding of iron homoeostasis and its biomedical consequences, suggesting that lifelong exposure to higher iron levels is likely associated with lower risk of anaemia-related disorders and higher risk of genitourinary, musculoskeletal, infectious and neoplastic diseases.

Original language	English
Article number	1631
Number of pages	17
Journal	Communications Biology
Volume	7
Issue number	1
DOIs	https://doi.org/10.1038/s42003-024-07115-3
Publication status	Published - 6 Dec 2024

Funding

Funders	Funder number
British Heart Foundation	RG/18/13/33946
NIHR Cambridge Biomedical Research Centre	BRC-1215-20014, NIHR203312
Medical Research Council
Engineering and Physical Sciences Research Council
Economic and Social Research Council, UK
Welsh Government
Public Health Agency
Wellcome Trust
Cancer Research UK	A27657
National Institute for Health and Care Research - Blood and Transplant Research Unit	NIHR203337
Rhodes Trust
Wellcome Trust	225790/Z/22/Z
Medical Research Council	MC_UU_00002/7
NIHR Cambridge Biomedical Research Centre	NIHR203312
National Institute for Health and Care Research
European Union	116074
Free University of Bozen-Bolzano
European Regional Development Fund	FESR1157
Azienda Ospedaliera di Verona
Medical Research Council
European Commission	LSHG-CT-2006018947
Ministry of Science, Education, and Sports	108-1080315-0302
Medical Research Council	U. MC_UU_00007/10
Independent Research Fund Denmark	09-069412, 0602-02634B
Independent Research Fund Denmark	09-069412, 0602-02634B
Novo Nordisk Foundation	NNF17OC0027594
Finnish Funding Agency for Technology and Innovation	3982/31/2013
Business Finland	HUS 4685/31/2016, UH 4386/31/2016
AbbVie
AstraZeneca
Biogen IDEC
Bristol-Myers Squibb
Genentech Incorporated
Merck Sharp Dohme LLC
Pfizer
GlaxoSmithKline
Sanofi US Services Inc.
Maze Therapeutics Inc
Janssen Research and Development
Novartis
Boehringer Ingelheim GmbH
Ministero della Salute	ICS110.1/RF97.71
National Institute on Aging	263MD9164, 263MD821336
Compagnia di San Paolo, Torino, Italy
Fondazione Cariplo
Fondazione Telethon
Ministero della Salute	RC 01/21
National Institute for Health and Care Research - Blood and Transplant Research Unit	NIHR BTRU-2014-10024
Medical Research Council	MR/L003120/1
British Heart Foundation	RG/18/13/33946, SP/09/002, RG/13/13/30194
NIHR Cambridge Biomedical Research Centre
Helmholtz Zentrum München - German Research Center for Environmental Health
Bavarian Health and Food Safety Authority
Dutch Kidney Foundation	E033
European Union	FP-6 LSHM CT 2006 037697
National Institutes of Health	2R01LM010098
Netherlands Organisation for Health Research and Development	175.010.2007.006, 916.761.70, 90.700.441
Federal Ministry of Education and Research

Keywords

Humans
Iron/metabolism
Homeostasis
Hepcidins/genetics
Receptors, Transferrin/genetics
Hemochromatosis Protein/genetics
Female
Mendelian Randomization Analysis
Male
Genome-Wide Association Study
Polymorphism, Single Nucleotide
Deficiency
Risk
Stores
Ferric carboxymaltose
Metaanalysis
Coronary-heart-disease
Association
Biobank
Mice
Failure

Access to Document

10.1038/s42003-024-07115-3

Cite this

Allara, E., Bell, S., Smith, R., Keene, S. J., Gill, D., Gaziano, L., Morselli Gysi, D., Wang, F., Tragante, V., Mason, A., Karthikeyan, S., Lumbers, R. T., Bonglack, E., Ouwehand, W., Roberts, D. J., Dowsett, J., Ostrowski, S. R., Larsen, M. H., Ullum, H., ... DBDS Genomic Consortium (2024). Novel loci and biomedical consequences of iron homoeostasis variation. Communications Biology, 7(1), Article 1631. https://doi.org/10.1038/s42003-024-07115-3

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title = "Novel loci and biomedical consequences of iron homoeostasis variation",

abstract = "Iron homoeostasis is tightly regulated, with hepcidin and soluble transferrin receptor (sTfR) playing significant roles. However, the genetic determinants of these traits and the biomedical consequences of iron homoeostasis variation are unclear. In a meta-analysis of 12 cohorts involving 91,675 participants, we found 43 genomic loci associated with either hepcidin or sTfR concentration, of which 15 previously unreported. Mapping to putative genes indicated involvement in iron-trait expression, erythropoiesis, immune response and cellular trafficking. Mendelian randomisation of 292 disease outcomes in 1,492,717 participants revealed associations of iron-related loci and iron status with selected health outcomes across multiple domains. These associations were largely driven by HFE, which was associated with the largest iron variation. Our findings enhance understanding of iron homoeostasis and its biomedical consequences, suggesting that lifelong exposure to higher iron levels is likely associated with lower risk of anaemia-related disorders and higher risk of genitourinary, musculoskeletal, infectious and neoplastic diseases.",

keywords = "Humans, Iron/metabolism, Homeostasis, Hepcidins/genetics, Receptors, Transferrin/genetics, Hemochromatosis Protein/genetics, Female, Mendelian Randomization Analysis, Male, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Deficiency, Risk, Stores, Ferric carboxymaltose, Metaanalysis, Coronary-heart-disease, Association, Biobank, Mice, Failure",

author = "Elias Allara and Steven Bell and Rebecca Smith and Keene, \{Spencer J\} and Dipender Gill and Liam Gaziano and \{Morselli Gysi\}, Deisy and Feiyi Wang and Vinicius Tragante and Amy Mason and Savita Karthikeyan and Lumbers, \{R Thomas\} and Emmanuela Bonglack and Willem Ouwehand and Roberts, \{David J\} and Joseph Dowsett and Ostrowski, \{Sisse Rye\} and Larsen, \{Margit H{\o}rup\} and Henrik Ullum and Pedersen, \{Ole Birger\} and S{\o}ren Brunak and Karina Banasik and Christian Erikstrup and Jonathan Mitchell and Christian Fuchsberger and Cristian Pattaro and Pramstaller, \{Peter P\} and Domenico Girelli and Mikko Arvas and Jarkko Toivonen and Sophie Molnos and Annette Peters and Ozren Polasek and Igor Rudan and Caroline Hayward and Ciara McDonnell and Nicola Pirastu and Wilson, \{James F\} and \{van den Hurk\}, Katja and Franke Quee and Luigi Ferrucci and Stefania Bandinelli and Toshiko Tanaka and Giorgia Girotto and Concas, \{Maria Pina\} and Alessandro Pecori and Niek Verweij and \{van der Harst\}, Pim and \{van de Vegte\}, \{Yordi J\} and \{Di Angelantonio\}, Emanuele and \{DBDS Genomic Consortium\}",

note = "{\textcopyright} 2024. The Author(s).",

year = "2024",

month = dec,

day = "6",

doi = "10.1038/s42003-024-07115-3",

language = "English",

volume = "7",

journal = "Communications Biology",

issn = "2399-3642",

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Allara, E, Bell, S, Smith, R, Keene, SJ, Gill, D, Gaziano, L, Morselli Gysi, D, Wang, F, Tragante, V, Mason, A, Karthikeyan, S, Lumbers, RT, Bonglack, E, Ouwehand, W, Roberts, DJ, Dowsett, J, Ostrowski, SR, Larsen, MH, Ullum, H, Pedersen, OB, Brunak, S, Banasik, K, Erikstrup, C, Mitchell, J, Fuchsberger, C, Pattaro, C, Pramstaller, PP, Girelli, D, Arvas, M, Toivonen, J, Molnos, S, Peters, A, Polasek, O, Rudan, I, Hayward, C, McDonnell, C, Pirastu, N, Wilson, JF, van den Hurk, K, Quee, F, Ferrucci, L, Bandinelli, S, Tanaka, T, Girotto, G, Concas, MP, Pecori, A, Verweij, N, van der Harst, P, van de Vegte, YJ, Di Angelantonio, E & DBDS Genomic Consortium 2024, 'Novel loci and biomedical consequences of iron homoeostasis variation', Communications Biology, vol. 7, no. 1, 1631. https://doi.org/10.1038/s42003-024-07115-3

TY - JOUR

T1 - Novel loci and biomedical consequences of iron homoeostasis variation

AU - Allara, Elias

AU - Bell, Steven

AU - Smith, Rebecca

AU - Keene, Spencer J

AU - Gill, Dipender

AU - Gaziano, Liam

AU - Morselli Gysi, Deisy

AU - Wang, Feiyi

AU - Tragante, Vinicius

AU - Mason, Amy

AU - Karthikeyan, Savita

AU - Lumbers, R Thomas

AU - Bonglack, Emmanuela

AU - Ouwehand, Willem

AU - Roberts, David J

AU - Dowsett, Joseph

AU - Ostrowski, Sisse Rye

AU - Larsen, Margit Hørup

AU - Ullum, Henrik

AU - Pedersen, Ole Birger

AU - Brunak, Søren

AU - Banasik, Karina

AU - Erikstrup, Christian

AU - Mitchell, Jonathan

AU - Fuchsberger, Christian

AU - Pattaro, Cristian

AU - Pramstaller, Peter P

AU - Girelli, Domenico

AU - Arvas, Mikko

AU - Toivonen, Jarkko

AU - Molnos, Sophie

AU - Peters, Annette

AU - Polasek, Ozren

AU - Rudan, Igor

AU - Hayward, Caroline

AU - McDonnell, Ciara

AU - Pirastu, Nicola

AU - Wilson, James F

AU - van den Hurk, Katja

AU - Quee, Franke

AU - Ferrucci, Luigi

AU - Bandinelli, Stefania

AU - Tanaka, Toshiko

AU - Girotto, Giorgia

AU - Concas, Maria Pina

AU - Pecori, Alessandro

AU - Verweij, Niek

AU - van der Harst, Pim

AU - van de Vegte, Yordi J

AU - Di Angelantonio, Emanuele

AU - DBDS Genomic Consortium

PY - 2024/12/6

Y1 - 2024/12/6

N2 - Iron homoeostasis is tightly regulated, with hepcidin and soluble transferrin receptor (sTfR) playing significant roles. However, the genetic determinants of these traits and the biomedical consequences of iron homoeostasis variation are unclear. In a meta-analysis of 12 cohorts involving 91,675 participants, we found 43 genomic loci associated with either hepcidin or sTfR concentration, of which 15 previously unreported. Mapping to putative genes indicated involvement in iron-trait expression, erythropoiesis, immune response and cellular trafficking. Mendelian randomisation of 292 disease outcomes in 1,492,717 participants revealed associations of iron-related loci and iron status with selected health outcomes across multiple domains. These associations were largely driven by HFE, which was associated with the largest iron variation. Our findings enhance understanding of iron homoeostasis and its biomedical consequences, suggesting that lifelong exposure to higher iron levels is likely associated with lower risk of anaemia-related disorders and higher risk of genitourinary, musculoskeletal, infectious and neoplastic diseases.

AB - Iron homoeostasis is tightly regulated, with hepcidin and soluble transferrin receptor (sTfR) playing significant roles. However, the genetic determinants of these traits and the biomedical consequences of iron homoeostasis variation are unclear. In a meta-analysis of 12 cohorts involving 91,675 participants, we found 43 genomic loci associated with either hepcidin or sTfR concentration, of which 15 previously unreported. Mapping to putative genes indicated involvement in iron-trait expression, erythropoiesis, immune response and cellular trafficking. Mendelian randomisation of 292 disease outcomes in 1,492,717 participants revealed associations of iron-related loci and iron status with selected health outcomes across multiple domains. These associations were largely driven by HFE, which was associated with the largest iron variation. Our findings enhance understanding of iron homoeostasis and its biomedical consequences, suggesting that lifelong exposure to higher iron levels is likely associated with lower risk of anaemia-related disorders and higher risk of genitourinary, musculoskeletal, infectious and neoplastic diseases.

KW - Humans

KW - Iron/metabolism

KW - Homeostasis

KW - Hepcidins/genetics

KW - Receptors, Transferrin/genetics

KW - Hemochromatosis Protein/genetics

KW - Female

KW - Mendelian Randomization Analysis

KW - Male

KW - Genome-Wide Association Study

KW - Polymorphism, Single Nucleotide

KW - Deficiency

KW - Risk

KW - Stores

KW - Ferric carboxymaltose

KW - Metaanalysis

KW - Coronary-heart-disease

KW - Association

KW - Biobank

KW - Mice

KW - Failure

U2 - 10.1038/s42003-024-07115-3

DO - 10.1038/s42003-024-07115-3

M3 - Article

C2 - 39643614

SN - 2399-3642

VL - 7

JO - Communications Biology

JF - Communications Biology

IS - 1

M1 - 1631

ER -

Novel loci and biomedical consequences of iron homoeostasis variation

Abstract

Funding

Keywords

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