TY - JOUR

T1 - rs641738C>T near MBOAT7 is associated with liver fat, ALT and fibrosis in NAFLD

T2 - A meta-analysis

AU - Teo, Kevin

AU - Abeysekera, Kushala W.M.

AU - Adams, Leon

AU - Aigner, Elmar

AU - Anstee, Quentin M.

AU - Banales, Jesus M.

AU - Banerjee, Rajarshi

AU - Basu, Priyadarshi

AU - Berg, Thomas

AU - Bhatnagar, Pallav

AU - Buch, Stephan

AU - Canbay, Ali

AU - Caprio, Sonia

AU - Chatterjee, Ankita

AU - Ida Chen, Yii Der

AU - Chowdhury, Abhijit

AU - Daly, Ann K.

AU - Datz, Christian

AU - de Gracia Hahn, Dana

AU - DiStefano, Johanna K.

AU - Dong, Jiawen

AU - Duret, Amedine

AU - Vreugdenhil, Anita

AU - Alisi, Anna

AU - Socha, Piotr

AU - Jańczyk, Wojciech

AU - Baumann, Ulrich

AU - Rajwal, Sanjay

AU - van Mourik, Indra

AU - Lacaille, Florence

AU - Dabbas, Myriam

AU - Kelly, Deirdre A.

AU - Nobili, Valerio

AU - Emdin, Connor

AU - Fairey, Madison

AU - Gerhard, Glenn S.

AU - Eiriksdottir, Gudny

AU - Garcia, Melissa E.

AU - Gudnason, Vilmundur

AU - Harris, Tamara B.

AU - Kim, Lauren J.

AU - Launer, Lenore J.

AU - Nalls, Michael A.

AU - Smith, Albert V.

AU - Clark, Jeanne M.

AU - Hernaez, Ruben

AU - Kao, W. H.Linda

AU - Mitchell, Braxton D.

AU - Shuldiner, Alan R.

AU - Tybjærg-Hansen, Anne

AU - EU-PNAFLD Investigators

AU - GOLD Consortium

N1 - Publisher Copyright: © 2020 European Association for the Study of the Liver

PY - 2021/1

Y1 - 2021/1

N2 - 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.

AB - 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.

KW - ALSPAC

KW - Diabetes

KW - Fibrosis

KW - MBOAT7

KW - NAFLD

KW - Triglyceride

U2 - 10.1016/j.jhep.2020.08.027

DO - 10.1016/j.jhep.2020.08.027

M3 - Journal article

C2 - 32882372

AN - SCOPUS:85095843742

VL - 74

SP - 20

EP - 30

JO - Journal of Hepatology, Supplement

JF - Journal of Hepatology, Supplement

SN - 0169-5185

IS - 1

ER -