Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically-characterised cohort

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Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically-characterised cohort

Anstee, Quentin M. (författare): Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom; Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom,Newcastle Univ, England; Newcastle Upon Tyne Hosp NHS Fdn Trust, England,Univ Milan, Italy

Darlay, Rebecca (författare): Population & Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom,Newcastle Univ, England

Cockell, Simon (författare): Bioinformatics Support Unit, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom,Newcastle Univ, England

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Meroni, Marica (författare): Department of Pathophysiology and Transplantation, University of Milan, Translational Medicine - Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy,Johannes Gutenberg Univ Mainz, Germany

Govaere, Olivier (författare): Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom,Newcastle Univ, England

Tiniakos, Dina (författare): Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom; Dept of Pathology, Aretaieio Hospital, National & Kapodistrian University of Athens, Greece,Newcastle Univ, England; Natl & Kapodistrian Univ Athens, Greece

Burt, Alastair D. (författare): Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom; Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, Australia,Newcastle Univ, England; Univ Adelaide, Australia

Bedossa, Pierre (författare): Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom,Newcastle Univ, England

Palmer, Jeremy (författare): Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom,Newcastle Univ, England

Liu, Yang-Lin (författare): Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom,Newcastle Univ, England

Aithal, Guruprasad P. (författare): NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK,Nottingham Univ Hosp NHS Trust, England; Univ Nottingham, England

Allison, Michael (författare): Liver Unit, Department of Medicine, Cambridge Biomedical Research Centre, Cambridge University NHS Foundation Trust, United Kingdom,Cambridge Univ NHS Fdn Trust, England

Yki-Järvinen, Hannele (författare): Department of Medicine, University of Helsinki, Helsinki, Finland & Helsinki University Hospital, Helsinki, Finland,Univ Helsinki, Finland; Helsinki Univ Hosp, Finland

Vacca, Michele (författare): Liver Unit, Department of Medicine, Cambridge Biomedical Research Centre, Cambridge University NHS Foundation Trust, United Kingdom; Department of Biochemistry and Wellcome Trust/MRC Institute of Metabolic Science, MRC Metabolic Diseases Unit, Metabolic Research Laboratories, University of Cambridge, UK,Cambridge Univ NHS Fdn Trust, England; Univ Cambridge, England; Univ Cambridge, England

Dufour, Jean-Francois (författare): University Clinic for Visceral Surgery and Medicine, University of Berne, Freiburgstrasse, Berne, Switzerland,Univ Bern, Switzerland

Invernizzi, Pietro (författare): Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano - Bicocca, Monza, Italy; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy,Univ Milano Bicocca, Italy; San Gerardo Hosp, Italy

Prati, Daniele (författare): Department of Pathophysiology and Transplantation, University of Milan, Translational Medicine - Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy,Univ Milan, Italy

Ekstedt, Mattias (författare): Linköpings universitet,Avdelningen för diagnostik och specialistmedicin,Medicinska fakulteten,Region Östergötland, Mag- tarmmedicinska kliniken

Kechagias, Stergios (författare): Linköpings universitet,Avdelningen för diagnostik och specialistmedicin,Medicinska fakulteten,Region Östergötland, Mag- tarmmedicinska kliniken

Francque, Sven (författare): Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium,Antwerp Univ Hosp, Belgium

Petta, Salvatore (författare): Sezione di Gastroenterologia, Dipartimento Promozione della Salute, Materno-Infantile, di Medicina Interna e Specialistica di Eccellenza "G. D'Alessandro", Università di Palermo, Palermo, Italy,Univ Palermo, Italy

Bugianesi, Elisabetta (författare): Department of Medical Sciences, Division of Gastro-Hepatology, A.O. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy,Univ Turin, Italy

Clement, Karine (författare): Sorbonne University, Inserm, Nutrition and obesity: Systemic approaches, Nutrition department, Pitié-Salpêtrière hospital, Assistance Publique-Hôpitaux de Paris, Paris, France,Sorbonne Univ, France

Ratziu, Vlad (författare): Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié Salpêtrière, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France,Sorbonne Univ, France

Schattenberg, Jörn M. (författare): NAFLD Research Center, Department of Medicine, University Medical Center of the Johannes Gutenberg University, Mainz, Germany

Valenti, Luca (författare): Department of Pathophysiology and Transplantation, University of Milan, Translational Medicine - Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy,Univ Milan, Italy

Day, Christopher P. (författare): Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom,Newcastle Univ, England

Cordell, Heather J. (författare): Population & Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom,Newcastle Univ, England

Daly, Ann K. (författare): Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom,Newcastle Univ, England

EPoS, Consortium Investigators (författare)

Oresic, Matej, 1967- (författare): Örebro universitet,Institutionen för medicinska vetenskaper

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(creator_code:org_t)

Elsevier, 2020
2020
Engelska.
Ingår i: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 73:3, s. 505-515

Relaterad länk:: https://doi.org/10.1...; visa fler...; http://www.journal-o...; https://urn.kb.se/re...; https://urn.kb.se/re...; https://liu.diva-por... (primary) (Raw object); https://urn.kb.se/re...; https://doi.org/10.1...; https://urn.kb.se/re...; visa färre...

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BACKGROUND AND AIMS: Genetic factors associated with non-alcoholic fatty liver disease (NAFLD) remain incompletely understood. To date, most GWAS studies have adopted radiologically assessed hepatic triglyceride content as reference phenotype and so cannot address steatohepatitis or fibrosis. We describe a genome-wide association study (GWAS) encompassing the full spectrum of histologically characterized NAFLD.METHODS: The GWAS involved 1483 European NAFLD cases and 17781 genetically-matched population controls. A replication cohort of 559 NAFLD cases and 945 controls was genotyped to confirm signals showing genome-wide or close to genome-wide significance.RESULTS: Case-control analysis identified signals showing p-values ≤ 5 x 10-8 at four locations (chromosome (chr) 2 GCKR/C2ORF16; chr4 HSD17B13; chr19 TM6SF2; chr22 PNPLA3) together with two other signals with p<1 x10-7 (chr1 near LEPR and chr8 near IDO2/TC1). Case-only analysis of quantitative traits steatosis, disease activity score, NAS and fibrosis showed that the PNPLA3 signal (rs738409) was genome-wide significantly associated with steatosis, fibrosis and NAS score and identified a new signal (PYGO1 rs62021874) with close to genome-wide significance for steatosis (p=8.2 x 10-8). Subgroup case-control analysis for NASH confirmed the PNPLA3 signal. The chr1 LEPR SNP also showed genome-wide significance for this phenotype. Considering the subgroup with advanced fibrosis (≥F3), the signals on chromosomes 2, 19 and 22 remained genome-wide significant. With the exception of GCKR/C2ORF16, the genome-wide significant signals replicated.CONCLUSIONS: This study confirms PNPLA3 as a risk factor for the full histological spectrum of NAFLD at genome-wide significance levels, with important contributions from TM6SF2 and HSD17B13. PYGO1 is a novel steatosis modifier, suggesting relevance of Wnt signalling pathways in NAFLD pathogenesis.

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Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically-characterised cohort

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