| Title: | Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration |
| Journal: | Journal of Hepatology |
| Published: | 19 Jun 2019 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/31226389/ |
| DOI: | https://doi.org/10.1016/j.jhep.2019.05.032 |
| URL: | http://www.journal-of-hepatology.eu/article/S0168827819303538/pdf |
Publication 4941
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Abstract
BACKGROUND & AIMS: Excess liver iron content is common and is linked to the risk of hepatic and extrahepatic diseases. We aimed to identify genetic variants influencing liver iron content and use genetics to understand its link to other traits and diseases.</p>
METHODS: First, we performed a genome-wide association study (GWAS) in 8,289 individuals from UK Biobank, whose liver iron level had been quantified by magnetic resonance imaging, before validating our findings in an independent cohort (n = 1,513 from IMI DIRECT). Second, we used Mendelian randomisation to test the causal effects of 25 predominantly metabolic traits on liver iron content. Third, we tested phenome-wide associations between liver iron variants and 770 traits and disease outcomes.</p>
RESULTS: We identified 3 independent genetic variants (rs1800562 [C282Y] and rs1799945 [H63D] in HFE and rs855791 [V736A] in TMPRSS6) associated with liver iron content that reached the GWAS significance threshold (p <5 × 10-8). The 2 HFE variants account for ∼85% of all cases of hereditary haemochromatosis. Mendelian randomisation analysis provided evidence that higher central obesity plays a causal role in increased liver iron content. Phenome-wide association analysis demonstrated shared aetiopathogenic mechanisms for elevated liver iron, high blood pressure, cirrhosis, malignancies, neuropsychiatric and rheumatological conditions, while also highlighting inverse associations with anaemias, lipidaemias and ischaemic heart disease.</p>
CONCLUSION: Our study provides genetic evidence that mechanisms underlying higher liver iron content are likely systemic rather than organ specific, that higher central obesity is causally associated with higher liver iron, and that liver iron shares common aetiology with multiple metabolic and non-metabolic diseases.</p>
LAY SUMMARY: Excess liver iron content is common and is associated with liver diseases and metabolic diseases including diabetes, high blood pressure, and heart disease. We identified 3 genetic variants that are linked to an increased risk of developing higher liver iron content. We show that the same genetic variants are linked to higher risk of many diseases, but they may also be associated with some health advantages. Finally, we use genetic variants associated with waist-to-hip ratio as a tool to show that central obesity is causally associated with increased liver iron content.</p>
19 Keywords
- Adult
- Aged
- Biomarkers
- Cohort Studies
- Female
- Genome-Wide Association Study
- Hemochromatosis
- Hemochromatosis Protein
- Hepcidins
- Humans
- Iron
- Liver
- Magnetic Resonance Imaging
- Male
- Mendelian Randomization Analysis
- Middle Aged
- Phenotype
- Polymorphism, Single Nucleotide
- United Kingdom
162 Authors
- Henry R. Wilman
- Constantinos A. Parisinos
- Naeimeh Atabaki-Pasdar
- Matt Kelly
- E. Louise Thomas
- Stefan Neubauer
- Christopher Jennison
- Beate Ehrhardt
- Patrick Baum
- Corinna Schoelsch
- Jan Freijer
- Rolf Grempler
- Ulrike Graefe-Mody
- Anita Hennige
- Christiane Dings
- Thorsten Lehr
- Nina Scherer
- Iryna Sihinecich
- Francois Pattou
- Violeta Raverdi
- Robert Caiazzo
- Fanelly Torres
- Helene Verkindt
- Andrea Mari
- Andrea Tura
- Toni Giorgino
- Roberto Bizzotto
- Philippe Froguel
- Amelie Bonneford
- Mickael Canouil
- Veronique Dhennin
- Caroline Brorsson
- Soren Brunak
- Federico De Masi
- Valborg Gudmundsdóttir
- Helle Pedersen
- Karina Banasik
- Cecilia Thomas
- Peter Sackett
- Hans-Henrik Staerfeldt
- Agnete Lundgaard
- Birgitte Nilsson
- Agnes Nielsen
- Gianluca Mazzoni
- Tugce Karaderi
- Simon Rasmussen
- Joachim Johansen
- Rosa Allesøe
- Andreas Fritsche
- Barbara Thorand
- Jurek Adamski
- Harald Grallert
- Mark Haid
- Sapna Sharma
- Martina Troll
- Jonathan Adam
- Jorge Ferrer
- Heather Eriksen
- Gary Frost
- Ragna Haussler
- Mun-gwan Hong
- Jochen Schwenk
- Mathias Uhlen
- Claudia Nicolay
- Imre Pavo
- Birgit Steckel-Hamann
- Melissa Thomas
- Kofi Adragni
- Han Wu
- Leen't Hart
- Slieker Roderick
- Nienke van Leeuwen
- Koen Dekkers
- Francesca Frau
- Johann Gassenhuber
- Bernd Jablonka
- Petra Musholt
- Hartmut Ruetten
- Joachim Tillner
- Tania Baltauss
- Oana Bernard Poenaru
- Nathalie de Preville
- Marianne Rodriquez
- Manimozhiyan Arumugam
- Kristine Allin
- Line Engelbrechtsen
- Torben Hansen
- Tue Hansen
- Annemette Forman
- Anna Jonsson
- Oluf Pedersen
- Avirup Dutta
- Josef Vogt
- Henrik Vestergaard
- Markku Laakso
- Tarja Kokkola
- Teemu Kuulasmaa
- Paul Franks
- Nick Giordano
- Hugo Pomares-Millan
- Hugo Fitipaldi
- Pascal Mutie
- Maria Klintenberg
- Margit Bergstrom
- Leif Groop
- Martin Ridderstrale
- Naeimeh Atabaki Pasdar
- Harshal Deshmukh
- Alison Heggie
- Dianne Wake
- Donna McEvoy
- Ian McVittie
- Mark Walker
- Andrew Hattersley
- Anita Hill
- Angus Jones
- Timothy McDonald
- Mandy Perry
- Rachel Nice
- Michelle Hudson
- Claire Thorne
- Emmanouil Dermitzakis
- Ana Viñuela
- Louise Cabrelli
- Heather Loftus
- Adem Dawed
- Louise Donnelly
- Ian Forgie
- Ewan Pearson
- Colin Palmer
- Andrew Brown
- Robert Koivula
- Agata Wesolowska-Andersen
- Moustafa Abdalla
- Nicky McRobert
- Juan Fernandez
- Yunlong Jiao
- Neil Robertson
- Stephen Gough
- Jane Kaye
- Miranda Mourby
- Anubha Mahajan
- Mark McCarthy
- Nisha Shah
- Harriet Teare
- Reinhard Holl
- Anitra Koopman
- Femke Rutters
- Joline Beulens
- Lenka Groeneveld
- Anitra Koopman
- Jimmy Bell
- Louise Thomas
- Brandon Whitcher
- Anubha Mahajan
- Aroon D. Hingorani
- Riyaz S. Patel
- Harry Hemingway
- Paul W. Franks
- Jimmy D. Bell
- Rajarshi Banerjee
- Hanieh Yaghootkar
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