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

JOURNAL OF HEPATOLOGY

卷:73

Article

Anstee, Quentin M.^1,2  Darlay, Rebecca³  Cockell, Simon⁴  Meroni, Marica⁵  Govaere, Olivier¹  Tiniakos, Dina^1,6  Burt, Alastair D.^1,7  Bedossa, Pierre¹  Palmer, Jeremy¹  Liu, Yang-Lin¹  Aithal, Guruprasad P.^8,9  Allison, Michael¹⁰  Yki-Jarvinen, Hannele^11,12  Vacca, Michele^10,13,14  Dufour, Jean-Francois¹⁵  Invernizzi, Pietro^16,17,25  Prati, Daniele⁵  Ekstedt, Mattias¹⁸  Kechagias, Stergios¹⁸  Francque, Sven¹⁹  Petta, Salvatore²⁰  Bugianesi, Elisabetta²¹  Clement, Karine²²  Ratziu, Vlad²³  Schattenberg, Joern M.²⁴  Valenti, Luca⁵  Day, Christopher P.¹  Cordell, Heather J.³  Daly, Ann K.¹ 

[1] Newcastle Univ, Fac Med Sci, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England

[2] Newcastle Upon Tyne Hosp NHS Fdn Trust, Newcastle NIHR Biomed Res Ctr, Newcastle Upon Tyne, Tyne & Wear, England

[3] Newcastle Univ, Fac Med Sci, Populat & Hlth Sci Inst, Newcastle Upon Tyne, Tyne & Wear, England

[4] Newcastle Univ, Fac Med Sci, Bioinformat Support Unit, Newcastle Upon Tyne, Tyne & Wear, England

[5] Univ Milan, Fdn IRCCS Ca Granda Osped Maggiore Policlin, Dept Pathophysiol & Transplantat, Translat Med, Milan, Italy

[6] Natl & Kapodistrian Univ Athens, Aretaieio Hosp, Dept Pathol, Athens, Greece

[7] Univ Adelaide, Fac Hlth & Med Sci, Adelaide, SA, Australia

[8] Nottingham Univ Hosp NHS Trust, NIHR Nottingham Biomed Res Ctr, Nottingham, England

[9] Univ Nottingham, Nottingham, England

[10] Cambridge Univ NHS Fdn Trust, Cambridge Biomed Res Ctr, Dept Med, Liver Unit, Cambridge, England

[11] Univ Helsinki, Dept Med, Helsinki, Finland

[12] Helsinki Univ Hosp, Helsinki, Finland

[13] Univ Cambridge, Dept Biochem, MRC Metab Dis Unit, MRC Inst Metab Sci,Metab Res Labs, Cambridge, England

[14] Univ Cambridge, Wellcome Trust, MRC Metab Dis Unit, MRC Inst Metab Sci,Metab Res Labs, Cambridge, England

[15] Univ Bern, Univ Clin Visceral Surg & Med, Freiburgstr, CH-3010 Bern, Switzerland

[16] Univ Milano Bicocca, Div Gastroenterol, Dept Med & Surg, Monza, Italy

[17] Univ Milano Bicocca, Ctr Autoimmune Liver Dis, Dept Med & Surg, Monza, Italy

[18] Linkoping Univ, Dept Med & Hlth Sci, Div Gastroenterol & Hepatol, Linkoping, Sweden

[19] Antwerp Univ Hosp, Dept Gastroenterol & Hepatol, Antwerp, Belgium

[20] Univ Palermo, Sez Gastroenterol, Dipartimento Promoz Salute Maternoinfantile Med I, Palermo, Italy

[21] Univ Turin, Dept Med Sci, Div Gastrohepatol, AO Citta Salute & Sci Torino, Turin, Italy

[22] Sorbonne Univ, Pitie Salpetriere Hosp, AP HP, INSERM,Nutr & Obes Syst Approaches,Nutr Dept, F-75013 Paris, France

[23] Sorbonne Univ, Hop Pitie Salpetriere, AP HP, Inst Cardiometab & Nutr ICAN, Paris, France

[24] Johannes Gutenberg Univ Mainz, NAFLD Res Ctr, Dept Med, Univ Med Ctr, Mainz, Germany

[25] San Gerardo Hosp, European Reference Network Hepatol Dis ERN RARE L, Monza, Italy

关键词: NAFLD;    NASH;    Fibrosis;    GWAS;    PNPLA3;    TM6SF2;    GCKR;    HSD17B13;    SNP;   

DOI  :  10.1016/j.jhep.2020.04.003

来源: Elsevier

【 摘 要 】

Background & Aims: Genetic factors associated with nonalcoholic fatty liver disease (NAFLD) remain incompletely understood. To date, most genome-wide association studies (GWASs) have adopted radiologically assessed hepatic triglyceride content as the reference phenotype and so cannot address steatohepatitis or fibrosis. We describe a GWAS encompassing the full spectrum of histologically characterised NAFLD. Methods: The GWAS involved 1,483 European NAFLD cases and 17,781 genetically matched 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 4 locations (chromosome [chr] 2 GCKR/C2ORF16; chr4 HSD17B13; chr19 TM6SF2; chr22 PNPLA3) together with 2 other signals with p <1 x 10(-7) (chr1 near LEPR and chr8 near IDO2/TC1). Case-only analysis of quantitative traits showed that the PNPLA3 signal (rs738409) had genome-wide significance for steatosis, fibrosis and NAFLD activity score and a new signal (PYGO1 rs62021874) had 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 single nucleotide polymorphism also showed genome-wide significance for this phenotype. Considering the subgroup with advanced fibrosis (>= F3), the signals on chr2, chr19 and chr22 maintained their genome-wide significance. Except for GCKR/C2ORF16, the genome-wide significance signals were 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 that Wnt signalling pathways may be relevant in NAFLD pathogenesis. Lay summary: Non-alcoholic fatty liver disease is a common disease where excessive fat accumulates in the liver and may result in cirrhosis. To understand who is at risk of developing this disease and suffering liver damage, we undertook a genetic study to compare the genetic profiles of people suffering from fatty liver disease with genetic profiles seen in the general population. We found that particular sequences in 4 different areas of the human genome were seen at different frequencies in the fatty liver disease cases. These sequences may help predict an individual's risk of developing advanced disease. Some genes where these sequences are located may also be good targets for future drug treatments. (C) 2020 European Association for the Study of the Liver. Published by Elsevier B.V.

【 授权许可】

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