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Variants in MBOAT7 locus show link to NAFLD

Researchers found the membrane bound O-acyltransferase domain-containing 7 gene rs641738 variant was linked to severe nonalcoholic fatty liver disease in people of European descent, according to published findings in Gastroenterology.

“We investigated whether MBOAT7-TMC4 is a susceptibility locus for the development and progression of NAFLD. … We found that the locus associated with increased hepatic fat content in two cohorts and with the entire spectrum of histological liver damage related to NAFLD,” the researchers wrote.

Researchers including Stefano Romeo, MD, PhD, of the department of molecular and clinical medicine, The Sahlgrenska Academy, University of Gothenburg, Sweden, genotyped rs641738 in DNA collected from 3,854 participants from the Dallas Heart Study, a multi-ethnic population-based probability sample of Dallas County residents, and 1,149 European participants from the Liver Biopsy Cross-sectional Cohort. The goal was to test their hypothesis that MBOAT7 and TMC4 is a susceptibility locus for NAFLD.

Overall, 2,736 participants from the Dallas Heart Study underwent proton magnetic resonance spectroscopy to measure hepatic triglyceride content, whereas 1,149 participants from the Liver Biopsy Cross-sectional Cohort underwent liver biopsy to diagnose liver disease and severity.

Of the participants, analyses showed that genotype rs641738 at the MBOAT7-TMC4 locus was associated with increased hepatic fat content, and with more severe liver damage and increased risk for fibrosis compared with participants without the genotype variant.

“This association seems to be mediated by changes in hepatic phosphatidylinositol acyl-chain remodeling,” the researchers wrote.

MBOAT7 was found to be highly expressed in the liver, whereas TMC4 was not.

Multivariate logistic analysis showed each T allele conferred an increased risk for steatosis (OR = 1.42; 95% CI, 1.07-1.91), nonalcoholic steatohepatitis (OR = 1.18; 95% CI, 1-1.4) and fibrosis stages 2 to 4 (OR = 1.3; 95% CI, 1.06-1.7) after adjusting for certain variables. The MBOAT7 rs641738 T allele was associated with lower protein expression in the liver and changes in plasma phosphatidylinositol (PI) species consistent with decreased MBOAT7 function.

A subset of 98 patients with obesity who had available data from liver biopsy due to bariatric surgery were also measured for the MBOAT7-TMC4 genes to determine “whether the mechanism whereby rs641738 variant predisposes to NAFLD by changing the gene expression,” according to the research. Among this cohort, the rs641738 T allele was associated with the presence of steatosis (P = .01) and severity of steatosis (P = .04). In addition, MBOAT7 mRNA levels were 20-fold higher than TMC4 mRNA levels (P < .001).

“We showed an association between variation in the MBOAT7 locus and the development and severity of NAFLD in individuals of European descent,” the researchers concluded. “Further studies are needed to understand whether rs641738 is the casual variant or is in linkage disequilibrium with a casual variant, and to elucidate the mechanism linking altered hepatic PI remodeling to NAFLD development and progression.” – by Melinda Stevens

Disclosure: The researchers report no relevant financial disclosures.