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.
Main Authors
Popovic, Relja Fabre, Margarete Schutzman, Jennifer Kulkarni, Diptee Porello, Alessandro Loboda, Andrey Lehtonen, Heli McDonough, Stefan Vuoti, Sauli Kaarniranta, Kai Turunen, Joni A. Ollila, Terhi Uusitalo, Hannu Karjalainen, Juha Liu, Mengzhen Loomis, Stephanie Strauss, Erich Chen, Hao Tasanen, Kaisa Huilaja, Laura Hannula-Jouppi, Katariina Salmi, Teea Peltonen, Sirkku Koulu, Leena Choy, David Wu, Ying Pussinen, Pirkko Salminen, Aino Salo, Tuula Rice, David Nieminen, Pekka Palotie, Ulla Siponen, Maria Suominen, Liisa Mäntylä, Päivi Gursoy, Ulvi Anttonen, Vuokko Sipilä, Kirsi Laivuori, Hannele Kurra, Venla Kotaniemi-Talonen, Laura Heikinheimo, Oskari Kalliala, Ilkka Aaltonen, Lauri Jokimaa, Varpu Vääräsmäki, Marja Uimari, Outi Morin-Papunen, Laure Niinimäki, Maarit Piltonen, Terhi Kivinen, Katja Widen, Elisabeth Tukiainen, Taru Välimäki, Niko Laakkonen, Eija Tyrmi, Jaakko Silven, Heidi Sliz, Eeva Arffman, Riikka Savukoski, Susanna Laisk, Triin Pujol, Natalia Kumar, Janet Hovatta, Iiris Isometsä, Erkki Ollila, Hanna Suvisaari, Jaana Mäkitie, Antti Bizaki-Vallaskangas, Argyro Toppila-Salmi, Sanna Willberg, Tytti Saarentaus, Elmo Aarnisalo, Antti Rahikkala, Elisa Aittomäki, Kristiina Åberg, Fredrik Kurki, Mitja Havulinna, Aki Mehtonen, Juha Palta, Priit Hassan, Shabbeer Parolo, Pietro Della, Briotta Zhou, Wei Maasha, Mutaamba Lemmelä, Susanna Rivas, Manuel Liu, Aoxing Lehisto, Arto Ganna, Andrea Llorens, Vincent Heyne, Henrike Rämö, Joel Rodosthenous, Rodos Strausz, Satu Palotie, Tuula Palin, Kimmo Garcia-Tabuenca, Javier Siirtola, Harri Kiiskinen, Tuomo Lee, Jiwoo Tsuo, Kristin Kristiansson, Kati Hyvärinen, Kati Ritari, Jarmo Pylkäs, Katri Karjalainen, Minna Mantere, Tuomo Kangasniemi, Eeva Heikkinen, Sami Pitkänen, Nina Lessard, Samuel Kallio, Lila Wahlfors, Tiina Punkka, Eero Siltanen, Sanna Kuopio, Teijo Jalanko, Anu Shen, Huei-Yi Kajanne, Risto Aavikko, Mervi Cooper, Helen Öller, Denise Leinonen, Rasko Palin, Henna Linna, Malla-Maria Kanai, Masahiro Zheng, Zhili Lahtela, L. Elisa Kaunisto, Mari Kilpeläinen, Elina Sipilä, Timo P. Dada, Oluwaseun Alexander Ghazal, Awaisa Kytölä, Anastasia Weldatsadik, Rigbe Donner, Kati Loukola, Anu Laiho, Päivi Sistonen, Tuuli Kaiharju, Essi Laukkanen, Markku Järvensivu, Elina Lähteenmäki, Sini Männikkö, Lotta Wong, Regis Toivola, Auli Brunfeldt, Minna Mattsson, Hannele Koskelainen, Sami Hiekkalinna, Tero Paajanen, Teemu Luo, Shuang Padmanabhuni, Shanmukha Sampath Niemi, Marianna Gracia-Tabuenca, Javier Helminen, Mika Luukkaala, Tiina Vähätalo, Iida Tammerluoto, Jyrki Smith, Sarah Southerington, Tom Lehto, Petri Djousse, Luc Cho, Kelly Inouye, Michael Burgess, Stephen Benyamin, Beben Oexle, Konrad Swinkels, Dorine Stefansson, Kari Magnusson, Magnus Gaziano, Michael Ivey, Kerry Danesh, John Pereira, Alexandre Wood, Angela M. Butterworth, Adam S. Di Angelantonio, Emanuele
Format
Articles Research article
Published
2024
Series
Subjects
Publication in research information system
Publisher
Nature Publishing Group
The permanent address of the publication
https://urn.fi/URN:NBN:fi:jyu-202412117738Use this for linking
Review status
Peer reviewed
ISSN
2399-3642
DOI
https://doi.org/10.1038/s42003-024-07115-3
Language
English
Published in
Communications Biology
Citation
  • Popovic, R., Fabre, M., Schutzman, J., Kulkarni, D., Porello, A., Loboda, A., Lehtonen, H., McDonough, S., Vuoti, S., Kaarniranta, K., Turunen, J. A., Ollila, T., Uusitalo, H., Karjalainen, J., Liu, M., Loomis, S., Strauss, E., Chen, H., Tasanen, K., . . . Di Angelantonio, E. (2024). Novel loci and biomedical consequences of iron homoeostasis variation. Communications Biology, 7, Article 1631. https://doi.org/10.1038/s42003-024-07115-3
License
CC BY 4.0Open Access
Additional information about funding
We would like to thank the individuals who participated in the study and whose contribution made this work possible. FinDonor_1 & FinDonor_2. These studies were supported by the Finnish Funding Agency for Technology and Innovation (Tekes) to the Salwe GID (Personalised Diagnostics and Care) programme (ID 3982/31/2013) and by the VTR funding from the Finnish Government. FinnGen. We want to acknowledge the participants and investigators of FinnGen study. The FinnGen project is funded by two grants from Business Finland (HUS 4685/31/2016 and UH 4386/31/2016) and the following industry partners: AbbVie Inc., AstraZeneca UK Ltd, Biogen MA Inc., Bristol Myers Squibb (and Celgene Corporation & Celgene International II Sàrl), Genentech Inc., Merck Sharp & Dohme LCC, Pfizer Inc., GlaxoSmithKline Intellectual Property Development Ltd., Sanofi US Services Inc., Maze Therapeutics Inc., Janssen Biotech Inc, Novartis AG, and Boehringer Ingelheim International GmbH.
Copyright© The Author(s) 2024

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