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

JOURNAL OF HEPATOLOGY

卷:74

Article

Teo, Kevin¹  Abeysekera, Kushala W. M.²  Adams, Leon^3,4  Aigner, Elmar⁵  Anstee, Quentin M.^6,7  Banales, Jesus M.⁸  Banerjee, Rajarshi⁹  Basu, Priyadarshi¹⁰  Berg, Thomas¹¹  Bhatnagar, Pallav¹²  Buch, Stephan¹³  Canbay, Ali¹⁴  Caprio, Sonia¹⁵  Chatterjee, Ankita¹⁰  Chen, Yii-Der Ida¹⁶  Chowdhury, Abhijit¹⁷  Daly, Ann K.⁶  Datz, Christian¹⁸  Hahn, Dana de Gracia¹  DiStefano, Johanna K.¹⁹  Dong, Jiawen¹  Duret, Amedine¹  Emdin, Connor²⁰  Fairey, Madison¹  Gerhard, Glenn S.²¹  Guo, Xiuqing¹⁶  Hampe, Jochen¹³  Hickman, Matthew²  Heintz, Lena²²  Hudert, Christian²³  Hunter, Harriet¹  Kelly, Matt⁹  Kozlitina, Julia²⁴  Krawczyk, Marcin^22,25  Lammert, Frank²²  Langenberg, Claudia²⁶  Lavine, Joel²⁷  Li, Lin²⁸  Lim, Hong Kai¹  Loomba, Rohit²⁹  Luukkonen, Panu K.^30,31,32,33  Melton, Phillip E.^34,35,36  Mori, Trevor A.³  Palmer, Nicholette D.³⁷  Parisinos, Constantinos A.³⁸  Pillai, Sreekumar G.¹²  Qayyum, Faiza³⁹  Reichert, Matthias C.²²  Romeo, Stefano^40,41,42  Rotter, Jerome I.¹⁶  Im, Yu Ri¹  Santoro, Nicola^15,43  Schafmayer, Clemens⁴⁴  Speliotes, Elizabeth K.^45,46  Stender, Stefan³⁹  Stickel, Felix⁴⁷  Still, Christopher D.⁴⁸  Strnad, Pavel⁴⁹  Taylor, Kent D.¹⁶  Tybjaerg-Hansen, Anne³⁹  Umano, Giuseppina Rosaria^15,50  Utukuri, Mrudula¹  Valenti, Luca^51,52  Wagenknecht, Lynne E.⁵³  Wareham, Nicholas J.²⁶  Watanabe, Richard M.⁵⁴  Wattacheril, Julia⁵⁵  Yaghootkar, Hanieh⁵⁶  Yki-Jarvinen, Hannele^30,31,32  Young, Kendra A.⁵⁷  Mann, Jake P.²⁶ 

[1] Univ Cambridge, Sch Clin Med, Cambridge, England

[2] Univ Bristol, MRC Integrat Epidemiol Unit IEU, Bristol, Avon, England

[3] Univ Western Australia, Med Sch, Fac Hlth & Med Sci, Perth, WA, Australia

[4] Sir Charles Gairdner Hosp, Dept Hepatol, Perth, WA, Australia

[5] Paracelsus Med Univ Salzburg, Dept Med 1, Salzburg, Austria

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

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

[8] Univ Basque Country UPV EHU, Biodonostia Hlth Res Inst, Dept Liver & Gastrointestinal Dis, Donostia Univ Hosp,CIBERehd,Ikerbasque, San Sebastian, Spain

[9] Perspectum Ltd, Oxford, England

[10] Natl Inst Biomed Genom, Kalyani, W Bengal, India

[11] Univ Leipzig, Dept Med 2, Div Hepatol, Med Ctr, Leipzig, Germany

[12] Eli Lilly & Co, Indianapolis, IN 46285 USA

[13] Tech Univ Dresden TU Dresden, Univ Hosp Dresden, Med Dept 1, Dresden, Germany

[14] Otto von Guericke Univ, Gastroenterol Hepatol & Infectiol, Magdeburg, Germany

[15] Yale Univ, Dept Pediat, New Haven, CT 06520 USA

[16] Harbor UCLA Med Ctr, Dept Pediat, Inst Translat Genom & Populat Sci, Lundquist Inst Biomed Innovat, Torrance, CA 90509 USA

[17] Inst Post Grad Med Educ & Res, Kolkata, India

[18] Paracelsus Med Univ Salzburg, Gen Hosp Oberndorf, Teaching Hosp, Dept Internal Med, Oberndorf, Austria

[19] Translat Genom Res Inst TGen, Diabet & Fibrot Dis Unit, Phoenix, AZ USA

[20] Broad Inst Harvard & MIT, Program Med & Populat Genet, Boston, MA USA

[21] Temple Univ, Lewis Katz Sch Med, Dept Med Genet & Mol Biochem, Philadelphia, PA 19122 USA

[22] Saarland Univ, Med Ctr, Dept Med 2, Homburg, Germany

[23] Charite Univ Med Berlin, Dept Pediat Gastroenterol, Berlin, Germany

[24] Univ Texas Southwestern Med Ctr Dallas, Eugene McDermott Ctr Human Growth & Dev, Dallas, TX 75390 USA

[25] Med Univ Warsaw, Dept Gen Transplant & Liver Surg, Ctr Preclin Res, Lab Metab Liver Dis, Warsaw, Poland

[26] Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England

[27] Columbia Univ, Dept Pediat, New York, NY 10027 USA

[28] BioStat Solut LLC, Frederick, MD USA

[29] Univ Calif San Diego, Div Gastroenterol & Epidemiol, NAFLD Res Ctr Div, La Jolla, CA 92093 USA

[30] Minerva Fdn, Helsinki, Finland

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

[32] Helsinki Univ Hosp, Helsinki, Finland

[33] Yale Univ, Sch Med, New Haven, CT USA

[34] Univ Western Australia, Fac Hlth & Med Sci, Sch Global Populat Hlth, Perth, WA, Australia

[35] Curtin Univ, Sch Pharm & Biomed Sci, Fac Hlth Sci, Perth, WA, Australia

[36] Univ Tasmania, Menzies Inst Med Res, Coll Hlth & Med, Hobart, Tas, Australia

[37] Wake Forest Sch Med, Dept Biochem, Winston Salem, NC 27101 USA

[38] UCL, Fac Populat Hlth Sci, Inst Hlth Informat, London, England

[39] Copenhagen Univ Hosp, Rigshospitalet, Dept Clin Biochem, Copenhagen, Denmark

[40] Univ Gothenburg, Dept Mol & Clin Med, Gothenburg, Sweden

[41] Sahlgrens Univ Hosp, Cardiol Dept, Gothenburg, Sweden

[42] Magna Graecia Univ Catanzaro, Dept Med & Surg Sci, Clin Nutr Unit, Catanzaro, Italy

[43] V Tiberio Univ Molise, Dept Med & Hlth Sci, Campobasso, Italy

[44] Univ Kiel, Dept Visceral & Thorac Surg, Kiel, Germany

[45] Univ Michigan Hlth Syst, Dept Med, Div Gastroenterol & Hepatol, Ann Arbor, MI USA

[46] Univ Michigan, Sch Med, Dept Computat Med & Bioinformat, Ann Arbor, MI USA

[47] Univ Hosp Zurich, Dept Gastroenterol & Hepatol, Zurich, Switzerland

[48] Geisinger Obes Inst, Danville, PA USA

[49] Univ Hosp RWTH Aachen, Med Clin 3, Aachen, Germany

[50] Univ Campania Luigi Vanvitelli, Dept Woman Child Gen & Specialized Surg, Naples, Italy

[51] Univ Milan, Dept Pathophysiol & Transplantat, Milan, Italy

[52] Fdn IRCCS Ca Granda Osped Maggiore Policlin Milan, Dept Transfus Med & Hematol, Translat Med, Milan, Italy

[53] Wake Forest Sch Med, Div Publ Hlth Sci, Winston Salem, NC 27101 USA

[54] Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90007 USA

[55] Columbia Univ, Coll Phys & Surg, Dept Med, Ctr Liver Dis & Transplantat,New York Presbyteria, New York, NY USA

[56] Univ Exeter, Coll Med & Hlth, Genet Complex Traits, Exeter, Devon, England

[57] Univ Colorado Denver, Colorado Sch Publ Hlth, Dept Epidemiol, Aurora, CO USA

关键词: MBOAT7;    Fibrosis;    NAFLD;    Triglyceride;    Diabetes;    ALSPAC;   

DOI  :  10.1016/j.jhep.2020.08.027

来源: Elsevier

【 摘 要 】

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], p(z) = 4.8x10(-5)) and diagnosis of NAFLD (odds ratio [OR] 1.17 [95% CI 1.05-1.3], p(z) = 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], p(z) = 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 (p(z) = 0.002) and lower serum triglycerides (p(z) = 1.5x10(-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. (C) 2020 European Association for the Study of the Liver. Published by Elsevier B.V.

【 授权许可】

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