Association of MTTP gene variants with pediatric NAFLD: A candidate-gene-based analysis of single nucleotide variations in obese children.

Dongling Dai,Feiqiu Wen,Zhe Su,Guosheng Liu,Shaoming Zhou,Jianli Zhou,Fusheng He,Mingbang Wang,Marco Giorgio Baroni

doi:10.1371/journal.pone.0185396

Abstract

ObjectiveWe used targeted next-generation sequencing to investigate whether genetic variants of lipid metabolism-related genes are associated with increased susceptibility to nonalcoholic fatty liver disease (NAFLD) in obese children.MethodsA cohort of 100 obese children aged 6 to 18 years were divided into NAFLD and non-NAFLD groups and subjected to hepatic ultrasound, anthropometric, and biochemical analyses. We evaluated the association of genetic variants with NAFLD susceptibility by investigating the single nucleotide polymorphisms in each of 36 lipid-metabolism-related genes. The panel genes were assembled for target region sequencing. Correlations between single nucleotide variations, biochemical markers, and clinical phenotypes were analyzed.Results97 variants in the 36 target genes per child were uncovered. Twenty-six variants in 16 genes were more prevalent in NAFLD subjects than in in-house controls. The mutation rate of MTTP rs2306986 and SLC6A2 rs3743788 was significantly higher in NAFLD subjects than in non-NAFLD subjects (OR: 3.879; P = 0.004; OR: 6.667, P = 0.005). Logistic regression analysis indicated the MTTP variant rs2306986 was an independent risk factor for NAFLD (OR: 23.468, P = 0.044).ConclusionsThe results of this study, examining a cohort of obese children, suggest that the genetic variation at MTTP rs2306986 was associated with higher susceptibility to NAFLD. This may contribute to the altered lipid metabolism by disruption of assembly and secretion of lipoprotein, leading to reducing fat export from the involved hepatocytes.

Highlights

The results of this study, examining a cohort of obese children, suggest that the genetic variation at MTTP rs2306986 was associated with higher susceptibility to Nonalcoholic fatty liver disease (NAFLD)
Nonalcoholic fatty liver disease (NAFLD) includes a range of liver diseases from simple fatty liver to nonalcoholic steatohepatitis (NASH), which can lead to fibrosis, cirrhosis, and hepatocellular carcinoma [1]
Studies on the offspring of participants suggest a genetic predisposition to developing NAFLD [4], and heritability studies [5, 6] showed that nonalcoholic fatty liver disease is heritable

Summary

Introduction

Nonalcoholic fatty liver disease (NAFLD) includes a range of liver diseases from simple fatty liver to nonalcoholic steatohepatitis (NASH), which can lead to fibrosis, cirrhosis, and hepatocellular carcinoma [1]. NAFLD is one of the most prevalent liver diseases among pediatric patients in developed countries owing to the increasing prevalence of obesity [2]. An increasing number of studies identify genes that contribute to the high risk for developing pediatric NAFLD. Studies on the offspring of participants suggest a genetic predisposition to developing NAFLD [4], and heritability studies [5, 6] showed that nonalcoholic fatty liver disease is heritable. Genome-wide association studies (GWAS) of NAFLD subjects in Western countries identified several gene variants associated with NAFLD [8]. Gene expression studies reported that some genetic variants were associated with NAFLD [9]

Methods

Results

Conclusion