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

Abstract

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 = 4.8×10 –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 = 1.5×10 –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.

Genetic predisposition similarities between NASH and ASH: Identification of new therapeutic targets

“…Furthermore, GCKR cannot be targeted to reduce liver fat because this would lead to hyperglycemia [47]. On the other hand, genetic variation of membrane bound O-acyltransferase domain-containing 7 (MBOAT7) has been linked to predisposition to hepatic fat accumulation in both to AFLD and NAFLD [31,50,51]. HSD17B13 variation (rs143404524 and rs72613567) has more recently been implicated in the protection against ASH and NASH, cirrhosis and HCC [52][53][54].…”

“…However, initial data are beginning to shed light on the qualitative alterations in liver fat (from lipidomics) and activation of intracellular pathways (from transcriptomics) that come with worsening FLD and are involved in disease progression. The most notable recent example is provided by the identification of the rs641738 C>T variant of MBOAT7 as a risk factor for FLD [31,50,51], and the discovery of the mechanism underlying the association [50,58,67]. Indeed, this discovery pinpointed a role for a specific lipid species (namely lysophosphatidyl-inositol, LPI), opening up new research avenues.…”

The Role of Diagnostic Biomarkers, Omics Strategies, and Single-Cell Sequencing for Nonalcoholic Fatty Liver Disease in Severely Obese Patients

“…Patients listed for bariatric surgery also constitute a particularly interesting cohort for evaluation of novel biomarkers, due to the easy access to peroperative liver tissue, and their massive, sustained weight loss post-surgery [44]. To date, further > 10 genetic variants have been associated with NAFLD [46,52]. The best validated are TM6SF2 (transmembrane 6 superfamily member 2), which may be required for normal VLDL secretion, while GCKR (glucokinase-regulator) regulates hepatocyte glucose metabolism.…”

“…To date, further >10 genetic variants have been associated with NAFLD [ 46 , 52 ]. The best validated are TM6SF2 (transmembrane 6 superfamily member 2), which may be required for normal VLDL secretion, while GCKR (glucokinase-regulator) regulates hepatocyte glucose metabolism.…”

Understanding the underlying molecular pathways by which Mboat7/Lpiat1 depletion induces hepatic steatosis

“…The common sequence variant rs641738 C>T near the MBOAT7 gene confers increased susceptibility to NAFLD and the entire spectrum of its conditions by downregulating MBOAT7 expression in the liver ( 3 ). In a recent meta-analysis of 42 studies including more than one million participants, this common variant has been firmly associated with the presence and severity of NAFLD in European adults ( 4 ). Interestingly, homozygotes for very rare and severe loss-of-function mutations in MBOAT7 display severe cognitive impairment with neurodevelopmental defects ( 5 ), showing how common and rare genetic variants in the same locus may lead to extremely diverse phenotypes.…”