The rs626283 Variant in the MBOAT7 Gene is Associated with Insulin Resistance and Fatty Liver in Caucasian Obese Youth

Abstract

Objectives: Non alcoholic fatty liver disease (NAFLD) is a leading cause of liver damage in childhood, its occurrence is influenced by genetic and environmental factors. Recently, the rs626283 polymorphism in the MBOAT7 gene has been found to be associated with alcoholic liver disease and NAFLD in adults.

Methods: In a multiethnic cohort of obese children and adolescents we genotyped the rs626283 polymorphism in the MBOAT7 gene, evaluated insulin sensitivity by an oral glucose tolerance test, and measured the intra-hepatic fat content (HFF%) by magnetic resonance imaging.

Results: In Caucasian youth, the minor allele (C) was associated with HFF% in (P=0.003), fasting insulin (P=0.03), area under the curve of glucose (P=0.03), and lower degree of whole-body insulin sensitivity (P=0.01) independent of age, gender, and body mass index z-score. A partial correlation showed that the association between the rs626283 variant and insulin resistance was driven by the presence of hepatic steatosis (P=0.009). However, there was no association between the rs626283 and hepatic steatosis among Hispanic and African American children and youth. The association between the rs626283 in the MBOAT7 gene among Caucasians was independent of the PNPLA3 rs738409, GCKR 1260326, and TM6SF2 rs58542926 (P=0.01). The four polymorphisms combined explained~19% of the HFF% in Caucasian obese children and adolescents.

Conclusions: The rs626283 variant in the MBOAT7 gene is associated with NAFLD and may affect glucose metabolism by modulating intra-hepatic fat content in Caucasian obese children and adolescents.

Figure 1.. Effect of rs626283 MBOAT7 gene variant on hepatic fat content and insulin sensitivity.

Association in Caucasians, African Americans, and Hispanics between MBOAT7 rs626283 single nucleotide polymorphism (SNP) and Whole Body Insulin Sensitivity Index (WBISI, panel A-C) and hepatic fat content (HFF, panel D-F). Light blue bars indicate the GG genotype group, the blue bars indicate the GC genotype group, and the dark blue bars indicate the CC genotype group. P values are adjusted for age, sex, and BMI Z-score. Data are shown as mean and SD.

Figure 2.. Joint effect of PNPLA3, TM6SF2, GCKR, and MBOAT7 on hepatic fat content.

Association between the genetic risk score calculated adding the risk alleles of rs738409 in the PNPLA3, the rs58542926 in the TM6SF2, the rs1260326 in the GCKR, and the rs626283 in the MBOAT7 and the Hepatic Fat Fraction (HFF%) in Caucasians. Panel A shows the association HFF% and genetic risk score without including the MBOAT7 genotype. Panel B shows the association HFF% and genetic risk score including the MBOAT7 genotype. P values are adjusted for age, sex, and BMI Z-score. Data are shown as mean values.