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Abstract

Background & aims: A common genetic variant near MBOAT7 (rs641738C>T) has been previously associated with hepatic fat and advanced histology in non-alcoholic fatty liver disease (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 characterize its role in the regulation of related metabolic phenotypes through meta-analysis. Methods: We performed meta-analysis of studies with data on the association between rs641738C>T genotype and: liver fat, NAFLD histology, and serum ALT, lipids, or insulin. These included directly genotyped studies and population-level data from genome-wide association studies (GWAS). We performed 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=4.8x10-5) and diagnosis of NAFLD (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=1.5x10-4). rs641738C>T was not associated with fasting insulin and no effect was observed in children with NAFLD.Conclusion: Our study validates rs641738C>T near MBOAT7 as a risk factor for the presence and severity of NAFLD in individuals of European descent.

Item Type:	Article
Authors/Creators:	Teo, K and Abeysekera, KWM and Adams, L and Aigner, E and Anstee, QM and Banales, JM and Banerjee, R and Basu, P and Berg, T and Bhatnagar, P and Buch, S and Canbay, A and Caprio, S and Chatterjee, A and Chen, Y-DI and Chowdhury, A and Daly, AK and Datz, C and Hahn, DG and DiStefano, JK and Dong, J and Duret, A and Emdin, C and Fairey, M and Gerhard, GS and Guo, X and Hampe, J and Hickman, M and Heintz, L and Hudert, C and Hunter, H and Kelly, M and Kozlitina, J and Krawczyk, M and Lammert, F and Langenberg, C and Lavine, J and Li, L and Lim, HK and Loomba, R and Luukkonen, PK and Melton, PE and Mori, TA and Palmer, ND and Parisinos, CA and Pillai, SG and Qayyum, F and Reichert, MC and Romeo, S and Rotter, JI and Im, YR and Santoro, N and Schafmayer, C and Speliotes, EK and Stender, S and Stickel, F and Still, CD and Strnad, P and Taylor, KD and Tybjaerg-Hansen, A and Umano, GR and Utukuri, M and Valenti, L and Wagenknecht, LE and Wareham, NJ and Watanabe, RM and Wattacheril, J and Yaghootkar, H and Yki-Jarvinen, H and Young, KA and Mann, JP
Keywords:	ALSPAC, MBOAT7, NAFLD, diabetes, fibrosis, triglyceride
Journal or Publication Title:	Journal of Hepatology
Publisher:	Elsevier Science Bv
ISSN:	0168-8278
DOI / ID Number:	https://doi.org/10.1016/j.jhep.2020.08.027
Copyright Information:	Copyright 2020 European Association for the Study of the Liver. Published by Elsevier B.V. This is an open access article under the CC BY license
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