Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration

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Wilman, H. R.Perspectum Diagnostics Ltd,University of Westminster (author)

Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration

Article/chapterEnglish2019

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Elsevier,2019
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LIBRIS-ID:oai:DiVA.org:kth-262512
https://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-262512URI
https://doi.org/10.1016/j.jhep.2019.05.032DOI
https://lup.lub.lu.se/record/61d10647-2504-43f7-91ab-9010f171cb62URI

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Language:English
Summary in:English

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Subject category:art swepub-publicationtype

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QC 20191128
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. 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. 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. 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. 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.

Subject headings and genre

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Gastroenterologi hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Gastroenterology and Hepatology hsv//eng
Genetics
Genome-wide association study
Iron
Magnetic resonance imaging
Metabolic syndrome
Metabolism
Genetics
Genome-wide association study
Iron
Magnetic resonance imaging
Metabolic syndrome
Metabolism

Added entries (persons, corporate bodies, meetings, titles ...)

Parisinos, C. A. (author)
Atabaki Pasdar, NaeimehLund University,Lunds universitet,Genetisk och molekylär epidemiologi,Forskargrupper vid Lunds universitet,Genetic and Molecular Epidemiology,Lund University Research Groups,Skåne University Hospital,Boehringer Ingelheim GmbH(Swepub:lu)med-nha (author)
Kelly, M. (author)
Thomas, E. L. (author)
Neubauer, S. (author)
Jennison, C. (author)
Ehrhardt, B. (author)
Baum, P. (author)
Schoelsch, C. (author)
Freijer, J. (author)
Grempler, R. (author)
Graefe-Mody, U. (author)
Hennige, A. (author)
Dings, C. (author)
Lehr, T. (author)
Scherer, N. (author)
Sihinecich, I. (author)
Pattou, F. (author)
Raverdi, V. (author)
Caiazzo, R. (author)
Torres, F. (author)
Verkindt, H. (author)
Mari, A. (author)
Tura, A. (author)
Giorgino, T. (author)
Froguel, P. (author)
Bonneford, A. (author)
Canouil, M. (author)
Dhennin, V. (author)
Brorsson, C. (author)
Brunak, S. (author)
De Masi, F. (author)
Gudmundsdóttir, V. (author)
Pedersen, H. (author)
Banasik, K. (author)
Thomas, C. (author)
Sackett, P. (author)
Staerfeldt, H. -H (author)
Lundgaard, A. (author)
Nilsson, B. (author)
Nielsen, A. (author)
Mazzoni, G. (author)
Karaderi, T. (author)
Rasmussen, S. (author)
Johansen, J. (author)
Allesøe, R. (author)
Fritsche, A. (author)
Thorand, B. (author)
Adamski, J. (author)
Grallert, H. (author)
Haid, M. (author)
Sharma, S. (author)
Troll, M. (author)
Adam, J. (author)
Ferrer, J. (author)
Eriksen, H. (author)
Frost, G. (author)
Häussler, Ragna S.KTH,Affinitets-proteomik,Science for Life Laboratory, SciLifeLab(Swepub:kth)u1izv3pd (author)
Hong, Mun-GwanKTH,Affinitets-proteomik,Science for Life Laboratory, SciLifeLab(Swepub:kth)u19gmsru (author)
Schwenk, Jochen M.KTH,Affinitets-proteomik,Science for Life Laboratory, SciLifeLab(Swepub:kth)u1h7wtme (author)
Uhlén, MathiasKTH,Affinitets-proteomik,Science for Life Laboratory, SciLifeLab(Swepub:kth)u1dulvmw (author)
Nicolay, C. (author)
Pavo, I. (author)
Steckel-Hamann, B. (author)
Thomas, M. (author)
Adragni, K. (author)
Wu, H. (author)
Hart, L. (author)
Roderick, S. (author)
van Leeuwen, N. (author)
Dekkers, K. (author)
Frau, F. (author)
Gassenhuber, J. (author)
Jablonka, B. (author)
Musholt, P. (author)
Ruetten, H. (author)
Tillner, J. (author)
Baltauss, T. (author)
Bernard Poenaru, O. (author)
de Preville, N. (author)
Rodriquez, M. (author)
Arumugam, M. (author)
Allin, K. (author)
Engelbrechtsen, L. (author)
Hansen, T. (author)
Forman, A. (author)
Jonsson, A. (author)
Pedersen, O. (author)
Dutta, A. (author)
Vogt, J. (author)
Vestergaard, H. (author)
Laakso, M. (author)
Kokkola, T. (author)
Kuulasmaa, T. (author)
Franks, PaulLund University,Lunds universitet,Genetisk och molekylär epidemiologi,Forskargrupper vid Lunds universitet,Genetic and Molecular Epidemiology,Lund University Research Groups,Skåne University Hospital(Swepub:lu)med-plf (author)
Giordano, N. (author)
Pomares-Millan, HugoLund University,Lunds universitet,Genetisk och molekylär epidemiologi,Forskargrupper vid Lunds universitet,Genetic and Molecular Epidemiology,Lund University Research Groups,Skåne University Hospital(Swepub:lu)hu7454po (author)
Fitipaldi, HugoLund University,Lunds universitet,Genetisk och molekylär epidemiologi,Forskargrupper vid Lunds universitet,Ortopedi - klinisk och molekylär osteoporosforskning,Genetic and Molecular Epidemiology,Lund University Research Groups,Orthopedics - Clinical and Molecular Osteoporosis Research,Skåne University Hospital(Swepub:lu)hu3745fi (author)
Mutie, PascalLund University,Lunds universitet,Genetisk och molekylär epidemiologi,Forskargrupper vid Lunds universitet,Genetic and Molecular Epidemiology,Lund University Research Groups,Skåne University Hospital(Swepub:lu)pa4264mu (author)
Klintenberg, MariaSkåne University Hospital(Swepub:lu)med-mk1 (author)
Bergstrom, M. (author)
Groop, L. (author)
Ridderstrale, M. (author)
Atabaki Pasdar, N. (author)
Deshmukh, H. (author)
Heggie, A. (author)
Wake, D. (author)
McEvoy, D. (author)
McVittie, I. (author)
Walker, M. (author)
Hattersley, A. (author)
Hill, A. (author)
Jones, A. (author)
McDonald, T. (author)
Perry, M. (author)
Nice, R. (author)
Hudson, M. (author)
Thorne, C. (author)
Dermitzakis, E. (author)
Viñuela, A. (author)
Cabrelli, L. (author)
Loftus, H. (author)
Dawed, A. (author)
Donnelly, L. (author)
Forgie, I. (author)
Pearson, E. (author)
Palmer, C. (author)
Brown, A. (author)
Koivula, R. (author)
Wesolowska-Andersen, A. (author)
Abdalla, M. (author)
McRobert, N. (author)
Fernandez, J. (author)
Jiao, Y. (author)
Robertson, N. (author)
Gough, S. (author)
Kaye, J. (author)
Mourby, M. (author)
Mahajan, A. (author)
McCarthy, M. (author)
Shah, N. (author)
Teare, H. (author)
Holl, R. (author)
Koopman, A. (author)
Rutters, F. (author)
Beulens, J. (author)
Groeneveld, L. (author)
Bell, J. (author)
Thomas, L. (author)
Whitcher, B. (author)
Hingorani, A. D. (author)
Patel, R. S. (author)
Hemingway, H. (author)
Franks, P. W. (author)
Bell, J. D. (author)
Banerjee, R. (author)
Yaghootkar, H.University of Westminster,University of Exeter (author)
Giordano, GiuseppeLund University,Lunds universitet,Genetisk och molekylär epidemiologi,Forskargrupper vid Lunds universitet,Genetic and Molecular Epidemiology,Lund University Research Groups,Skåne University Hospital(Swepub:lu)med-geg (author)
Perspectum Diagnostics LtdUniversity of Westminster (creator_code:org_t)

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In:Journal of Hepatology: Elsevier71:3, s. 594-6020168-82781600-0641

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By the author/editor: Wilman, H. R.; Parisinos, C. A.; Atabaki Pasdar, ...; Kelly, M.; Thomas, E. L.; Neubauer, S.; show more...; Jennison, C.; Ehrhardt, B.; Baum, P.; Schoelsch, C.; Freijer, J.; Grempler, R.; Graefe-Mody, U.; Hennige, A.; Dings, C.; Lehr, T.; Scherer, N.; Sihinecich, I.; Pattou, F.; Raverdi, V.; Caiazzo, R.; Torres, F.; Verkindt, H.; Mari, A.; Tura, A.; Giorgino, T.; Froguel, P.; Bonneford, A.; Canouil, M.; Dhennin, V.; Brorsson, C.; Brunak, S.; De Masi, F.; Gudmundsdóttir, ...; Pedersen, H.; Banasik, K.; Thomas, C.; Sackett, P.; Staerfeldt, H. - ...; Lundgaard, A.; Nilsson, B.; Nielsen, A.; Mazzoni, G.; Karaderi, T.; Rasmussen, S.; Johansen, J.; Allesøe, R.; Fritsche, A.; Thorand, B.; Adamski, J.; Grallert, H.; Haid, M.; Sharma, S.; Troll, M.; Adam, J.; Ferrer, J.; Eriksen, H.; Frost, G.; Häussler, Ragna ...; Hong, Mun-Gwan; Schwenk, Jochen ...; Uhlén, Mathias; Nicolay, C.; Pavo, I.; Steckel-Hamann, ...; Thomas, M.; Adragni, K.; Wu, H.; Hart, L.; Roderick, S.; van Leeuwen, N.; Dekkers, K.; Frau, F.; Gassenhuber, J.; Jablonka, B.; Musholt, P.; Ruetten, H.; Tillner, J.; Baltauss, T.; Bernard Poenaru, ...; de Preville, N.; Rodriquez, M.; Arumugam, M.; Allin, K.; Engelbrechtsen, ...; Hansen, T.; Forman, A.; Jonsson, A.; Pedersen, O.; Dutta, A.; Vogt, J.; Vestergaard, H.; Laakso, M.; Kokkola, T.; Kuulasmaa, T.; Franks, Paul; Giordano, N.; Pomares-Millan, ...; Fitipaldi, Hugo; Mutie, Pascal; Klintenberg, Mar ...; Bergstrom, M.; Groop, L.; Ridderstrale, M.; Atabaki Pasdar, ...; Deshmukh, H.; Heggie, A.; Wake, D.; McEvoy, D.; McVittie, I.; Walker, M.; Hattersley, A.; Hill, A.; Jones, A.; McDonald, T.; Perry, M.; Nice, R.; Hudson, M.; Thorne, C.; Dermitzakis, E.; Viñuela, A.; Cabrelli, L.; Loftus, H.; Dawed, A.; Donnelly, L.; Forgie, I.; Pearson, E.; Palmer, C.; Brown, A.; Koivula, R.; Wesolowska-Ander ...; Abdalla, M.; McRobert, N.; Fernandez, J.; Jiao, Y.; Robertson, N.; Gough, S.; Kaye, J.; Mourby, M.; Mahajan, A.; McCarthy, M.; Shah, N.; Teare, H.; Holl, R.; Koopman, A.; Rutters, F.; Beulens, J.; Groeneveld, L.; Bell, J.; Thomas, L.; Whitcher, B.; Hingorani, A. D.; Patel, R. S.; Hemingway, H.; Franks, P. W.; Bell, J. D.; Banerjee, R.; Yaghootkar, H.; Giordano, Giusep ...; show less...

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