| Title: | Quantifying risk modifiers of hereditary hemochromatosis using genomic and electronic health record data |
| Journal: | JHEP Reports |
| Published: | 6 Feb 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41861673/ |
| DOI: | https://doi.org/10.1016/j.jhepr.2026.101774 |
Publication 18347
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Abstract
BACKGROUND & AIMS: Hereditary hemochromatosis is an autosomal recessive disorder of excessive iron accumulation. Early diagnosis enables treatment before organ damage. The C282Y variant in the HFE gene is the main cause, but its penetrance of only 20% limits its utility for population-wide screening. We aimed to identify and quantify novel genetic and non-genetic modifiers of C282Y-related disease from electronic healthcare records, and thereby partly explain its incomplete penetrance.</p>
METHODS: We carried out a cohort study on data from 420,543 individuals in the FinnGen project, for whom genotype information and healthcare records were available. We performed both standard and interaction genome-wide association study analyses for hemochromatosis and fitted statistical models including age, sex, 21 million genetic variants, preceding diagnoses, and blood donation history as predictors. Results were validated using data from the UK Biobank.</p>
RESULTS: We identified three novel fine-mapped variants within 4 Mb of the HFE gene. Of these, variant rs181949568 in the CASC15 gene remained significant in the multivariable model (odds ratio 7.25, 95% CI 3.63-28.87, p = 1.96 × 10-8). We found that donating blood at least twice a year is likely sufficient to reduce the risk of C282Y homozygotes (male risk 0.16, 80% CI 0.13-0.19) to that of C282Y-H63D compound heterozygotes (male risk 0.018, 80% CI 0.015-0.023). Additionally, the S65C variant protects against severe disease (incidence ratio 0.328, 95% CI 0.192-0.562).</p>
CONCLUSIONS: We demonstrated that use of large-scale electronic health record data allows for precise quantification of individual-level risk, which we present as risk tables to support clinical practice. Furthermore, our findings suggest that hemochromatosis may be under-recognized in Finland.</p>
IMPACT AND IMPLICATIONS: Because the factors influencing the penetrance of the C282Y variant in hemochromatosis remain incompletely understood, a study leveraging newly available large-scale healthcare and genetic data is warranted. We present the findings of our study as an individual-level risk table designed for practicing clinicians, summarizing the combined effects of key variables most frequently observed in the dataset. Our results suggest that asymptomatic individuals who are homozygous for C282Y could significantly reduce their risk of developing hemochromatosis by donating blood just twice a year.</p>
461 Authors
- Jarkko Toivonen
- Jonna Clancy
- Aarno Palotie
- Mark Daly
- Bridget Riley-Gills
- Howard Jacob
- Coralie Viollet
- Slavé Petrovski
- Alix Berton
- Santha Ramakrishnan
- Ellen Tsai
- Zhihao Ding
- Emily Holzinger
- Robert Plenge
- Joseph Maranville
- Mark McCarthy
- Rion Pendergrass
- Jonathan Davitte
- Chia-Yen Chen
- Melis Atalar Aksit
- Anna Vlahiotis
- Katherine Klinger
- Clement Chatelain
- Jorg Blankenstein
- Karol Estrada
- Robert Graham
- Dawn Waterworth
- Chris O´Donnell
- Nicole Renaud
- Tomi P. Mäkelä
- Jaakko Kaprio
- Minna Ruddock
- Lila Kallio
- Antti Hakanen
- Terhi Kilpi
- Markus Perola
- Jukka Partanen
- Taneli Raivio
- Eero Punkka
- Teija Kekonen
- Raisa Serpi
- Kati Kristiansson
- Sanna Siltanen
- Veli-Matti Kosma
- Arto Mannermaa
- Jari Laukkanen
- Tiina Jokela
- Mervi Ahlroth
- Johanna Mäkelä
- Outi Tuovila
- Jeffrey Waring
- Bridget Riley-Gillis
- Fedik Rahimov
- Ioanna Tachmazidou
- Slavé Petrovski
- Alix Berton
- Santha Ramakrishnan
- Ellen Tsai
- Zhihao Ding
- Marc Jung
- Hanati Tuoken
- Shameek Biswas
- Benjamin Sun
- Rion Pendergrass
- Jonathan Davitte
- Neha Raghavan
- Jae-Hoon Sul
- Melis Atalar Aksit
- Xinli Hu
- Katherine Klinger
- Robert Graham
- Dawn Waterworth
- Nicole Renaud
- Ma´en Obeidat
- Jonathan Chung
- Jonas Zierer
- Mari Niemi
- Samuli Ripatti
- Johanna Schleutker
- Markus Perola
- Tiina Wahlfors
- Mikko Arvas
- Olli Carpén
- Reetta Hinttala
- Johannes Kettunen
- Arto Mannermaa
- Katriina Aalto-Setälä
- Mika Kähönen
- Jari Laukkanen
- Johanna Mäkelä
- Hanna Kujala
- Triin Laisk
- Natalia Pujol
- Mika Kähönen
- Veikko Salomaa
- Jaana Suvisaari
- Satu Koskela
- Jouni Lauronen
- Kristiina Aittomäki
- Pirkko Pussinen
- Tuomo Meretoja
- Heikki Joensuu
- Peeter Karihtala
- Emma Juuri
- Aino Salminen
- Tuula Salo
- David Rice
- Pekka Nieminen
- Ulla Palotie
- Fredrik Åberg
- Daniel Gordin
- Patrik Finne
- Joni A. Turunen
- Minna Raivio
- Pentti Tienari
- Martti Färkkilä
- Jukka Koskela
- Sampsa Pikkarainen
- Kari Eklund
- Paula Kauppi
- Daniel Gordin
- Juha Sinisalo
- Marja-Riitta Taskinen
- Tiinamaija Tuomi
- Timo Hiltunen
- Johanna Mattson
- Eveliina Salminen
- Terhi Ollila
- Katariina Hannula-Jouppi
- Oskari Heikinheimo
- Ilkka Kalliala
- Lauri Aaltonen
- Erkki Isometsä
- Antti Aarnisalo
- Ilkka Immonen
- Salla Ranta
- Filip Scheperjans
- Felix Vaura
- Nina Mars
- Esa Pitkänen
- Hannele Laivuori
- Katja Kivinen
- Elisabeth Widen
- Taru Tukiainen
- Hanna Ollila
- Elmo Saarentaus
- Anne Kerola
- Eero Vuoksimaa
- Joni Lindbohm
- Zhiyu Yang
- Matthew Sampson
- Adrian Banerji
- Michelle McNulty
- Aoxing Liu
- Joel Rämö
- Austin Argentieri
- Amanda Elliott
- Elisa Rahikkala
- Kirsi Sipilä
- Valtteri Julkunen
- Ville Leinonen
- Sanna Toppila-Salmi
- Mikko Hiltunen
- Eino Solje
- Hannu Kankaanranta
- Antti Mäkitie
- Iiris Hovatta
- Niko Välimäki
- Minttu Marttila
- Anne Portaankorva
- Eija Laakkonen
- Heidi Silven
- Eeva Sliz
- Riikka Arffman
- Susanna Savukoski
- Riitta Kaarteenaho
- Jaakko Tyrmi
- Laura Kuusalo
- Laura Pirilä
- Tapio Hellman
- Matti Vuori
- Teemu Niiranen
- Timo Blomster
- Johanna Huhtakangas
- Terttu Harju
- Kaisa Tasanen
- Laura Huilaja
- Vuokko Anttonen
- Marja Vääräsmäki
- Outi Uimari
- Laure Morin-Papunen
- Maarit Niinimäki
- Terhi Piltonen
- Reetta Kälviäinen
- Valtteri Julkunen
- Hilkka Soininen
- Mikko Kiviniemi
- Oili Kaipiainen-Seppänen
- Margit Pelkonen
- Päivi Auvinen
- Maria Siponen
- Liisa Suominen
- Päivi Mäntylä
- Kai Kaarniranta
- Jukka Peltola
- Airi Jussila
- Katri Kaukinen
- Pia Isomäki
- Jussi Hernesniemi
- Annika Auranen
- Hannu Uusitalo
- Teea Salmi
- Venla Kurra
- Laura Kotaniemi-Talonen
- Argyro Bizaki-Vallaskangas
- Juha Rinne
- Roosa Kallionpää
- Markku Voutilainen
- Antti Palomäki
- Laura Pirilä
- Riitta Lahesmaa
- Kaj Metsärinne
- Jenni Aittokallio
- Klaus Elenius
- Sirkku Peltonen
- Leena Koulu
- Ulvi Gursoy
- Varpu Jokimaa
- Tytti Willberg
- Adam Ziemann
- Nizar Smaoui
- Anne Lehtonen
- Apinya Lertratanakul
- Relja Popovic
- Mengzhen Liu
- Anneke Den Hollander
- Jan Freudenberg
- Britney Milkovich
- Andrew Blumenfeld
- Tushar Kumar
- Dirk Paul
- Bram Prins
- Eleanor Wheeler
- Kousik Kundu
- Santosh Atanur
- Andrew Lowe
- Thomas Spargo
- Oliver Burren
- Margarete Fabre
- Fabio Baschiera
- Hans van Leeuwen
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- Karl Heilbron
- Martin Rao
- Nicole Schmidt
- Samu Kurki
- Johanna Mielke
- Juho Immonen
- Thomas Battram
- Tobias Hogrebe
- Susan Eaton
- Ketian Yu
- Stephanie Loomis
- Coro Paisan-Ruiz
- Elke Markert
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- Tim Lu
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- Linda McCarthy
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- Chris Floyd
- Dan Swerdlow
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- Prerak Desai
- Stephen Haddad
- Damien Croteau-Chonka
- Billy Fahy
- Paola Bronson
- Kirsi Auro
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- Sauli Vuoti
- Dermot Reilly
- Karen He
- Ekaterina Khramtsova
- Amy Hart
- Meijian Guan
- Alessandro Porello
- P. Dunnmon
- Sara Gale
- Brice Keyes
- John Kwon
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- Matt Loza
- Chris Whelan
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- Yanfei Zhang
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- Andrei Popescu
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- Risto Kajanne
- Mervi Aavikko
- Helen Cooper
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