rs641738C>T nearMBOAT7is positively associated with liver fat, ALT, and histological severity of NAFLD: a meta-analysis
Authors: Teo Kevin , Abeysekera Kushala W. M. , Adams Leon , Aigner Elmar , Banales Jesus M. , Banerjee Rajarshi , Basu Priyadarshi , Berg Thomas , Bhatnagar Pallav , Buch Stephan , Canbay Ali , Caprio Sonia , Chatterjee Ankita , Chen Yii-Der Ida , Chowdhury Abhijit , Datz Christian , de Gracia Hahn Dana , DiStefano Johanna K. , Dong Jiawen , Duret Amedine ,   EU-PNAFLD Investigators, Emdin Connor , Fairey Madison , Gerhard Glenn S ,   GOLD Consortium, Guo Xiuqing , Hampe Jochen , Hickman Matthew , Heintz Lena , Hudert Christian , Hunter Harriet , Kelly Matt , Kozlitina Julia , Krawczyk Marcin , Lammert Frank , Langenberg Claudia , Lavine Joel , Li Lin , Lim Hong Kai , Loomba Rohit , Luukkonen Panu K. , Melton Phillip E. , Mori Trevor A. , Palmer Nicholette D. , Parisinos Constantinos A. , Pillai Sreekumar G , Qayyum Faiza , Reichert Matthias C. , Romeo Stefano , Rotter Jerome I. , Im Yu Ri , Santoro Nicola , Schafmayer Clemens , Speliotes Elizabeth K. , Stender Stefan , Stickel Felix , Still Christopher D. , Strnad Pavel , Taylor Kent D. , Tybjærg-Hansen Anne , Umano Giuseppina Rosaria , Utukuri Mrudula , Valenti Luca , Wagenknecht Lynne E. , Wareham Nicholas J. , Watanabe Richard M. , Wattacheril Julia , Yaghootkar Hanieh , Yki-Järvinen Hannele , Young Kendra A. , Mann Jake P. 
Published: December 2019

Background & Aims

A common genetic variant nearMBOAT7(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 1,047,265 participants (8,303 with liver biopsies) across 42 studies was 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]) and diagnosis of NAFLD (OR 1.22 [95% CI 1.08 - 1.39]) in Caucasian adults. The variant was also positively associated with presence of severe steatosis, NASH, and advanced fibrosis (OR: 1.32 [95% CI: 1.06 - 1.63]) 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.

Conclusion

Our study validates rs641738C>T nearMBOAT7as a risk factor for the presence and severity of NAFLD in individuals of European descent.