rs641738C>T nearMBOAT7is positively associated with liver fat, ALT, and histological severity of 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 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 characterise 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=1.5x10-4). 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.

Remodeling of Mitochondrial Plasticity: The Key Switch from NAFLD/NASH to HCC

“…Data were collected from 1047.265 subjects, of whom 8303 had liver biopsies, and displayed a correlation between the T minor allele and hepatic fat deposition, ALT levels, and advanced stages of NAFLD, such as fibrosis and HCC. In particular, carriers of the rs641738 variant show a 30% risk of developing HCC compared to non-carriers [ 203 ]. Physiologically, MBOAT7 localizes on MAMs and mediates phosphatidylinositol (PI) acyl-chain remodeling in the Land’s cycle.…”

Remodeling of Mitochondrial Plasticity: The Key Switch from NAFLD/NASH to HCC

“…Data were collected from 1047.265 subjects, of whom 8303 had liver biopsies, and displayed a correlation between the T minor allele and hepatic fat deposition, ALT levels and advanced stages of NAFLD, like fibrosis and HCC. In particular, carriers of the rs641738 variant show the 30% risk to develop HCC compared to non-carriers [207].…”

Genetic predisposition in metabolic‐dysfunction‐associated fatty liver disease and cardiovascular outcomes—Systematic review

“…A recent meta‐analysis with 131,096 participants (including 4174 children) out of which 7692 subjects had liver biopsy with histopathological assessment and 45,419 subjects had imagistic evaluation demonstrated that minor T allele of rs641738C > T was associated with elevated hepatic steatosis evaluated using computed tomography (CT)/magnetic resonance imaging (MRI) that was assessed by an additive genetic model (+0.05 standard deviations [95% CI: 0.01‐0.09], P = .025) 33 . Moreover, an increased risk of NAFLD (per‐allele OR: 1.09 [95% CI: 1.01‐1.17]), nonalcoholic steatohepatitis (OR: 1.11 [95% CI: 1.02‐1.21]), advanced fibrosis (OR: 1.14 [95% CI: 1.05‐1.23]) and HCC (OR: 1.43 [95% CI: 1.22‐1.67]) in adults with NAFLD was documented without any difference between Caucasians and non‐Caucasians sub‐group analysis.…”

“…Subsequently, multiple studies demonstrated that it is involved in the pathogenesis of several hepatic diseases including MAFLD independent of obesity, 25 as well as HCC 27 and fibrosis development in chronic viral hepatitis B and C infections 28‐31 . Nevertheless, the current literature contains conflicting data associating the genetic variant near MBOAT7 (rs641738C > T) polymorphism with an increased risk of developing MAFLD 32,33 …”