Communications Biology (Dec 2024)
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,
- DBDS Genomic Consortium,
- 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,
- Lambertus A. Kiemeney,
- Fred C. Sweep,
- Tessel E. Galesloot,
- Patrick Sulem,
- Daniel Gudbjartsson,
- Egil Ferkingstad,
- FinnGen Consortium,
- Luc Djousse,
- Kelly Cho,
- Michael Inouye,
- Stephen Burgess,
- Beben Benyamin,
- Konrad Oexle,
- Dorine Swinkels,
- Kari Stefansson,
- Magnus Magnusson,
- Andrea Ganna,
- Michael Gaziano,
- Kerry Ivey,
- John Danesh,
- Alexandre Pereira,
- Angela M. Wood,
- Adam S. Butterworth,
- Emanuele Di Angelantonio
Affiliations
- Elias Allara
- BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge
- Steven Bell
- Precision Breast Cancer Institute, Department of Oncology, University of Cambridge
- Rebecca Smith
- BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge
- Spencer J. Keene
- BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge
- Dipender Gill
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London
- Liam Gaziano
- BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge
- Deisy Morselli Gysi
- Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System
- Feiyi Wang
- Genetic Epidemiology Lab, Institute for Molecular Medicine Finland
- Vinicius Tragante
- deCODE genetics/Amgen Inc.
- Amy Mason
- BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge
- Savita Karthikeyan
- BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge
- R. Thomas Lumbers
- UCL Institute of Health Informatics
- Emmanuela Bonglack
- BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge
- Willem Ouwehand
- Department of Haematology, University of Cambridge
- David J. Roberts
- Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital
- Joseph Dowsett
- Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet
- Sisse Rye Ostrowski
- Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet
- Margit Hørup Larsen
- Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet
- Henrik Ullum
- Statens Serum Institut
- Ole Birger Pedersen
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen
- Søren Brunak
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen
- Karina Banasik
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen
- Christian Erikstrup
- Department of Immunology, Aarhus University Hospital
- DBDS Genomic Consortium
- Jonathan Mitchell
- Eurac Research, Institute for Biomedicine
- Christian Fuchsberger
- Eurac Research, Institute for Biomedicine
- Cristian Pattaro
- Eurac Research, Institute for Biomedicine
- Peter P. Pramstaller
- Eurac Research, Institute for Biomedicine
- Domenico Girelli
- Department of Medicine, Section of Internal Medicine, EuroBloodNet Referral Center, University Hospital of Verona
- Mikko Arvas
- Finnish Red Cross Blood Service
- Jarkko Toivonen
- Finnish Red Cross Blood Service
- Sophie Molnos
- msg life central europe gmbh
- Annette Peters
- Institute of Epidemiology, Helmholtz Munich
- Ozren Polasek
- Faculty of Medicine, University of Split
- Igor Rudan
- Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh
- Caroline Hayward
- Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh
- Ciara McDonnell
- Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh
- Nicola Pirastu
- Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh
- James F. Wilson
- Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh
- Katja van den Hurk
- Donor Studies, Department of Donor Medicine Research, Sanquin Research
- Franke Quee
- Donor Studies, Department of Donor Medicine Research, Sanquin Research
- Luigi Ferrucci
- Longitudinal studies section, National Institute on Aging
- Stefania Bandinelli
- Geriatric Unit, Azienda Sanitaria Firenze (ASF)
- Toshiko Tanaka
- Longitudinal studies section, National Institute on Aging
- Giorgia Girotto
- Institute for Maternal and Child Health - IRCCS, Burlo Garofolo
- Maria Pina Concas
- Institute for Maternal and Child Health - IRCCS, Burlo Garofolo
- Alessandro Pecori
- Institute for Maternal and Child Health - IRCCS, Burlo Garofolo
- Niek Verweij
- Department of Cardiology, University of Groningen, University Medical Center Groningen
- Pim van der Harst
- Department of Cardiology, University of Groningen, University Medical Center Groningen
- Yordi J. van de Vegte
- Department of Cardiology, University of Groningen, University Medical Center Groningen
- Lambertus A. Kiemeney
- IQ Health, Radboud University Medical Center
- Fred C. Sweep
- Department of Laboratory Medicine, Radboud University Medical Center
- Tessel E. Galesloot
- IQ Health, Radboud University Medical Center
- Patrick Sulem
- deCODE genetics/Amgen Inc.
- Daniel Gudbjartsson
- deCODE genetics/Amgen Inc.
- Egil Ferkingstad
- deCODE genetics/Amgen Inc.
- FinnGen Consortium
- Luc Djousse
- Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System
- Kelly Cho
- Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System
- Michael Inouye
- BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge
- Stephen Burgess
- BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge
- Beben Benyamin
- Australian Centre for Precision Health & Allied Health and Human Performance, University of South Australia
- Konrad Oexle
- Neurogenetic Systems Analysis Group, Institute of Neurogenomics, Helmholtz Munich
- Dorine Swinkels
- Department of Laboratory Medicine, Radboud University Medical Center
- Kari Stefansson
- deCODE genetics/Amgen Inc.
- Magnus Magnusson
- deCODE genetics/Amgen Inc.
- Andrea Ganna
- Genetic Epidemiology Lab, Institute for Molecular Medicine Finland
- Michael Gaziano
- Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System
- Kerry Ivey
- Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System
- John Danesh
- BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge
- Alexandre Pereira
- Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System
- Angela M. Wood
- BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge
- Adam S. Butterworth
- BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge
- Emanuele Di Angelantonio
- BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge
- DOI
- https://doi.org/10.1038/s42003-024-07115-3
- Journal volume & issue
-
Vol. 7,
no. 1
pp. 1 – 17
Abstract
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.
