rs641738C>T near MBOAT7 is associated with liver fat, ALT and fibrosis in NAFLD : A meta-analysis

Publisher Copyright: © 2020 European Association for the Study of the Liver Funding text 1 J.P.M. is supported by a Wellcome Trust Fellowship ( 216329/Z/19/Z ), a European Paediatric Research Society award and a Children's Liver Disease Foundation grant. The EU-PNAFLD is supported by an EASL Registry Grant . NIH grants: R01HD028016 (S.C.), R01DK111038 (S.C)., R01DK114504 (N.S.), DK091601 (J.K.D.) and UL1TR001105 (J.K.). Supported by the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) ( U01DK061718 , U01DK061728 , U01DK061731 , U01DK061732 , U01DK061734 , U01DK061737 , U01DK061738 , U01DK061730 , and U01DK061713 ); the National Center for Advancing Translational Sciences ( UL1TR000439 , UL1TR000436 , UL1TR000006 , UL1TR000448 , UL1TR000100 , UL1TR000004 , UL1TR000423 , UL1TR000058 , and UL1TR001881 ); and the NIDDK ( DK063491 to the Southern California Diabetes Endocrinology Research Center). This study was supported by the German Federal Ministry for Education and Research (BmBF) through the Livers Systems Medicine (LiSyM) project. This work was supported by grants from the Swiss National Funds (SNF no. 310030_169196 ) and the Swiss Foundation for Alcohol Research (SSA) to F.S. This Raine Study was supported by the National Health and Medical Research Council of Australia (grant numbers 403981 , 353514 and 572613 ). The UK Medical Research Council and Wellcome (grant ref: 102215/2/13/2 ) and the University of Bristol provide core support for ALSPAC. ALSPAC GWAS data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe . A comprehensive list of grants funding is available on the ALSPAC website ( www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf ); this research was specifically funded by grants from MRC and Alcohol Research UK ( MR/L022206/1 ) and NIH ( 5R01AA018333-05 ) to K.W.M.A. and M.H. L.V. was supported by MyFirst Grant AIRC n.16888, Ricerca Finalizzata Ministero della Salute RF-2016-02364358 , Ricerca corrente Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico . German Federal Ministry of Education and Research (BMBF LiSyM 031L0051 to F.L.). P.L. is supported by grants from the Sigrid Jusélius Foundation and the Novo Nordisk Foundation . The Fenland study was funded by grants to the MRC Epidemiology Unit ( MC UU12015/1 , MC UU 12015/5 ). R.B. and M.K. are employees of and shareholders in Perspectum Diagnostics Ltd. C.A.P. is funded by a Wellcome Trust Clinical PhD Programme ( 206274/Z/17/Z ). J.M.B. is supported by the Spanish Carlos III Health Institute (ISCIII; PI15/01132 , PI18/01075 , CIBERehd, and Miguel Servet Program CON14/00129) co-financed by Fondo Europeo de Desarrollo Regional (FEDER) and La Caixa Scientific Foundation ( HR17-00601 ). Research from the GUARDIAN Study was supported DK085175 and DK118062, and phenotyping in IRASFS was supported by HL060944, HL061019, HL060919 and HL060894 IRASFS from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). H.Y. is funded by a Diabetes UK RD Lawrence fellowship ( 17/0005594 ). Q.M.A. and A.D. supported by the EPoS (Elucidating Pathways of Steatohepatitis) consortium funded by the Horizon 2020 Framework Program of the European Union under Grant Agreement 634413 . Q.M.A., A.D., L.V. and A.G. are members of the LITMUS (Liver Investigation: Testing Biomarker Utility in Steatohepatitis) consortium funded by the European Union Innovative Medicines Initiative 2 (IMI2) Joint Undertaking under grant agreement 777377. Q.M.A. is a Newcastle NIHR Biomedical Research Center Investigator. Funding text 2 J.P.M. is supported by a Wellcome Trust Fellowship (216329/Z/19/Z), a European Paediatric Research Society award and a Children's Liver Disease Foundation grant. The EU-PNAFLD is supported by an EASL Registry Grant. NIH grants: R01HD028016 (S.C.), R01DK111038 (S.C)., R01DK114504 (N.S.), DK091601 (J.K.D.) and UL1TR001105 (J.K.). Supported by the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (U01DK061718, U01DK061728, U01DK061731, U01DK061732, U01DK061734, U01DK061737, U01DK061738, U01DK061730, and U01DK061713); the National Center for Advancing Translational Sciences (UL1TR000439, UL1TR000436, UL1TR000006, UL1TR000448, UL1TR000100, UL1TR000004, UL1TR000423, UL1TR000058, and UL1TR001881); and the NIDDK (DK063491 to the Southern California Diabetes Endocrinology Research Center). This study was supported by the German Federal Ministry for Education and Research (BmBF) through the Livers Systems Medicine (LiSyM) project. This work was supported by grants from the Swiss National Funds (SNF no. 310030_169196) and the Swiss Foundation for Alcohol Research (SSA) to F.S. This Raine Study was supported by the National Health and Medical Research Council of Australia (grant numbers 403981, 353514 and 572613). The UK Medical Research Council and Wellcome (grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. ALSPAC GWAS data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. A comprehensive list of grants funding is available on the ALSPAC website (www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf); this research was specifically funded by grants from MRC and Alcohol Research UK (MR/L022206/1) and NIH (5R01AA018333-05) to K.W.M.A. and M.H. L.V. was supported by MyFirst Grant AIRC n.16888, Ricerca Finalizzata Ministero della Salute RF-2016-02364358, Ricerca corrente Fondazione IRCCS Ca? Granda Ospedale Maggiore Policlinico. German Federal Ministry of Education and Research (BMBF LiSyM 031L0051 to F.L.). P.L. is supported by grants from the Sigrid Jus?lius Foundation and the Novo Nordisk Foundation. The Fenland study was funded by grants to the MRC Epidemiology Unit (MC UU12015/1, MC UU 12015/5). R.B. and M.K. are employees of and shareholders in Perspectum Diagnostics Ltd. C.A.P. is funded by a Wellcome Trust Clinical PhD Programme (206274/Z/17/Z). J.M.B. is supported by the Spanish Carlos III Health Institute (ISCIII; PI15/01132, PI18/01075, CIBERehd, and Miguel Servet Program CON14/00129) co-financed by Fondo Europeo de Desarrollo Regional (FEDER) and La Caixa Scientific Foundation (HR17-00601). Research from the GUARDIAN Study was supported DK085175 and DK118062, and phenotyping in IRASFS was supported by HL060944, HL061019, HL060919 and HL060894 IRASFS from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). H.Y. is funded by a Diabetes UK RD Lawrence fellowship (17/0005594). Q.M.A. and A.D. supported by the EPoS (Elucidating Pathways of Steatohepatitis) consortium funded by the Horizon 2020 Framework Program of the European Union under Grant Agreement 634413. Q.M.A., A.D., L.V. and A.G. are members of the LITMUS (Liver Investigation: Testing Biomarker Utility in Steatohepatitis) consortium funded by the European Union Innovative Medicines Initiative 2 (IMI2) Joint Undertaking under grant agreement 777377. Q.M.A. is a Newcastle NIHR Biomedical Research Center Investigator. Funding text 3 The authors are grateful to the Raine Study participants and their families, and to the Raine Study research staff for cohort coordination and data collection. The authors gratefully acknowledge the following institutes for providing funding for Core Management of the Raine Study: The University of Western Australia (UWA), Curtin University, the Raine Medical Research Foundation, the UWA Faculty of Medicine, Dentistry and Health Sciences, the Telethon Kids Institute, the Women and Infants Research Foundation (King Edward Memorial Hospital), and Edith Cowan University). We are extremely grateful to all the families who took part in the ALSPAC study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. This study was conducted using data from the Fenland study. The authors gratefully acknowledge the help of the MRC Epidemiology Unit Support Teams, including Field, Laboratory, and Data Management Teams. The authors are grateful to the members of the EU-PNAFLD Registry, including Anita Vreugdenhil, Anna Alisi, Piotr Socha, Wojciech Jańczyk, Ulrich Baumann, Sanjay Rajwal, Indra van Mourik, Florence Lacaille, Myriam Dabbas, Deirdre A. Kelly, and the late Valerio Nobili. The authors are also grateful to the members of the GOLD consortium: Gudny Eiriksdottir, Melissa E. Garcia, Vilmundur Gudnason, Tamara B. Harris, Lauren J. Kim, Lenore J. Launer, Michael A. Nalls, Albert V. Smith,Jeanne M. Clark, Ruben Hernaez, W. H. Linda Kao, Braxton D. Mitchell, Alan R. Shuldiner, Laura M. Yerges-Armstrong, Ingrid B. Borecki, J. Jeffrey Carr, Mary F. Feitosa, Jun Wu, Johannah L. Butler, Caroline S. Fox, Joel N. Hirschhorn, Udo Hoffmann, Shih-Jen Hwang, Joseph M. Massaro, Christopher J. O'Donnell, Cameron D. Palmer, Dushyant V. Sahani, Elizabeth K. Speliotes. We would also like to thank Naga Chalasani for his helpful comments. This research made use of the UK Biobank resource under project number 9914.Background & Aims: A common genetic variant near MBOAT7 (rs641738C>T) has been previously associated with hepatic fat and advanced histology in NAFLD; however, these findings have not been consistently replicated in the literature. We aimed to establish whether rs641738C>T is a risk factor across the spectrum of NAFLD and to characterise its role in the regulation of related metabolic phenotypes through a meta-analysis. Methods: We performed a meta-analysis of studies with data on the association between rs641738C>T genotype and liver fat, NAFLD histology, and serum alanine aminotransferase (ALT), lipids or insulin. These included directly genotyped studies and population-level data from genome-wide association studies (GWAS). We performed a random effects meta-analysis using recessive, additive and dominant genetic models. Results: Data from 1,066,175 participants (9,688 with liver biopsies) across 42 studies were included in the meta-analysis. rs641738C>T was associated with higher liver fat on CT/MRI (+0.03 standard deviations [95% CI 0.02–0.05], pz = 4.8×10–5) and diagnosis of NAFLD (odds ratio [OR] 1.17 [95% CI 1.05–1.3], pz = 0.003) in Caucasian adults. The variant was also positively associated with presence of advanced fibrosis (OR 1.22 [95% CI 1.03–1.45], pz = 0.021) in Caucasian adults using a recessive model of inheritance (CC + CT vs. TT). Meta-analysis of data from previous GWAS found the variant to be associated with higher ALT (pz = 0.002) and lower serum triglycerides (pz = 1.5×10–4). rs641738C>T was not associated with fasting insulin and no effect was observed in children with NAFLD. Conclusions: Our study validates rs641738C>T near MBOAT7 as a risk factor for the presence and severity of NAFLD in individuals of European descent. Lay summary: Fatty liver disease is a common condition where fat builds up in the liver, which can cause liver inflammation and scarring (including ‘cirrhosis’). It is closely linked to obesity and diabetes, but some genes are also thought to be important. We did this study to see whether one specific change (‘variant’) in one gene (‘MBOAT7’) was linked to fatty liver disease. We took data from over 40 published studies and found that this variant near MBOAT7 is linked to more severe fatty liver disease. This means that drugs designed to work on MBOAT7 could be useful for treating fatty liver disease.Peer reviewe