The MBOAT7-TMC4 Variant rs641738 Increases Risk of Nonalcoholic Fatty Liver Disease in Individuals of European Descent

Abstract

Background & Aims Nonalcoholic fatty liver disease (NAFLD) is a leading cause of liver damage and is characterized by steatosis. Genetic factors increase risk for progressive NAFLD. A genome-wide association study showed that the rs641738 C>T variant in the locus that contains the membrane bound O-acyltransferase domain-containing 7 gene (MBOAT7, also called LPIAT1) and transmembrane channel-like 4 gene (TMC4) increased the risk for cirrhosis in alcohol abusers. We investigated whether the MBOAT7/TMC4 is a susceptibility locus for the development and progression of NAFLD. Methods We genotyped rs641738 in DNA collected from 3854 participants from the Dallas Heart Study (a multi-ethnic population-based probability sample of Dallas County residents) and 1149 European individuals from the Liver Biopsy Cross-sectional Cohort. Clinical and anthropometric data were collected, and biochemical and lipidomics were measured in plasma samples from participants. A total of 2736 participants from the Dallas Heart Study underwent also proton magnetic resonance spectroscopy to measure hepatic triglyceride content. In the Liver Biopsy Cross-sectional Cohort, a total of 1149 individuals underwent liver biopsy to diagnose liver disease and disease severity. Results The genotype rs641738 at the MBOAT7/TMC4 locus associated with increased hepatic fat content in the 2 cohorts, and with more severe liver damage and increased risk of fibrosis compared to subjects without the variant. MBOAT7, but not TMC4, was found to be highly expressed in the liver. The MBOAT7 rs641738 T allele was associated with lower protein expression in the liver and changes in plasma phosphatidylinositol species consistent with decreased MBOAT7 function. Conclusions We provide evidence for an association between the MBOAT7 rs641738 variant and the development and severity of NAFLD in individuals of European descent. This association seems to be mediated by changes in the hepatic phosphatidylinositol acyl-chain remodeling.

PNPLA3 gene in liver diseases

“…Interestingly, the previous in silico analyses have also suggested that MBOAT7 could trigger arachidonic acid release and thus promote HCC-linked phenotypes, such as inflammation and fibrogenesis [45,98]. This hypothesis is in line with recent studies reporting higher levels of proinflammatory metabolites of arachidonic acid in patients with NASH [99], just as was observed in the association between a variant in MBOAT7 and increased risk of liver damage in ALD/NAFLD patients [30,100]. Overall, these observations highlight that PNPLA3, and more generally lipid turnover, may impact liver carcinogenesis.…”

Protein phosphatase 1 regulatory subunit 3B gene variation protects against hepatic fat accumulation and fibrosis in individuals at high risk of nonalcoholic fatty liver disease

“…The liver biopsy cohort (LBC) has been described 5, 15. A total of 1,388 adult individuals of European descent were consecutively enrolled from the Metabolic Liver Diseases outpatient service and bariatric surgery center, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano, Milan, Italy, and from the Northern Savo Hospital District, Kuopio, Finland.…”

“…The LBC cohort was genotyped for the rs738409 C>G ( PNPLA3 I148M), rs58542926 C>T (TM6SF2 E167K), rs1260326 C>T ( GCKR P446L), rs641738 C>T MBOAT7 , and rs4841132 G>A ( LOC157273‐PPP1R3B ) variants as described 5, 15. Genotyping of the LBC was performed in duplicate using TaqMan 5′‐nuclease assays (Life Technologies, Carlsbad, CA).…”

“…Dietary factors, such as alcohol, fructose, and physical activity, are other major risk factors for this condition 3. NAFLD has a strong genetic component, and variants in proteins regulating hepatocellular lipid handling, including patatin‐like phospholipase domain‐containing 3 ( PNPLA3 ), transmembrane 6 superfamily member 2 ( TM6SF2 ), membrane bound O‐acyltransferase domain‐containing 7 ( MBOAT7 ), and glucokinase regulator ( GCKR ), predispose to the development and progression to nonalcoholic steatohepatitis (NASH), which is the inflammatory form of NAFLD, and to hepatic fibrosis,4, 5 which is the major prognostic determinant in patients with NAFLD 6. By exploiting naturally occurring variation at these loci, we recently highlighted by a Mendelian randomization approach that hepatic fat accumulation is a key driver of liver disease progression and fibrosis development in at‐risk individuals 7.…”

Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention

“…PNPLA3 is presented as minor allele frequency (that is, the fre quency at which the second most common PNPLA3 allele occurs in a population). Among the emerging newly discovered risk loci, variants near the genes encoding for membrane bound O acyltransferase domain containing 7 (MBOAT7) and transmembrane channel like 4 (TMC4) have been shown to be associated with development and severity of NAFLD in patients of European descent 101 . Similarly, within the Latino popu lation in South America, the TM6SF2 Glu167Lys and PNPLA3 Ile148Met protein variants seem to confer susceptibility to progressive NASH 102 .…”