The Association of PNPLA3 Variants with Liver Enzymes in Childhood Obesity Is Driven by the Interaction with Abdominal Fat

Emanuele Miraglia Del Giudice,Nicola Santoro,Anna Grandone,Laura Perrone,Alessandra Amato,Piera Savarese,Pierluigi Marzuillo,Grazia Cirillo,Carmine Brienza,Jonatan R Ruiz

doi:10.1371/journal.pone.0027933

Emanuele Miraglia Del Giudice, Nicola Santoro + Show 8 more

Open Access

https://doi.org/10.1371/journal.pone.0027933

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Journal: PLoS ONE	Publication Date: Nov 28, 2011
Citations: 116	License type: CC BY 4.0

Affiliation: Yale University, University of Naples Federico II

Abstract

Background and AimsA polymorphism in adiponutrin/patatin-like phospholipase-3 gene (PNPLA3), rs738409 C->G, encoding for the I148M variant, is the strongest genetic determinant of liver fat and ALT levels in adulthood and childhood obesity. Aims of this study were i) to analyse in a large group of obese children the role of the interaction of not-genetic factors such as BMI, waist circumference (W/Hr) and insulin resistance (HOMA-IR) in exposing the association between the I148M polymorphism and ALT levels and ii) to stratify the individual risk of these children to have liver injury on the basis of this gene-environment interaction.Methods1048 Italian obese children were investigated. Anthropometric, clinical and metabolic data were collected and the PNPLA3 I148M variant genotyped.ResultsChildren carrying the 148M allele showed higher ALT and AST levels (p = 0.000006 and p = 0.0002, respectively). Relationships between BMI-SDS, HOMA-IR and W/Hr with ALT were analysed in function of the different PNPLA3 genotypes. Children 148M homozygous showed a stronger correlation between ALT and W/Hr than those carrying the other genotypes (p: 0.0045) and, therefore, 148M homozygotes with high extent of abdominal fat (W/Hr above 0.62) had the highest OR (4.9, 95% C. I. 3.2–7.8, p = 0.00001) to develop pathologic ALT.ConclusionsWe have i) showed for the first time that the magnitude of the association of PNPLA3 with liver enzymes is driven by the size of abdominal fat and ii) stratified the individual risk to develop liver damage on the basis of the interaction between the PNPLA3 genotype and abdominal fat.

Highlights

Children and adolescents are becoming increasingly vulnerable to obesity [1]
The spectrum of non alcoholic fatty liver disease (NAFLD) ranges from simple steatosis to steatosis associated with inflammation and fibrosis, which can eventually progress to liver cirrhosis [3]
In line with the data on obese subjects, we report in a group of 1048 Italian obese children and adolescents that the patatin-like phospholipase-3 gene (PNPLA3) rs738409 polymorphism was associated with ALT levels in a dosedependent manner

Summary

Introduction

Children and adolescents are becoming increasingly vulnerable to obesity [1]. Paralleling childhood obesity, non alcoholic fatty liver disease (NAFLD) is rapidly becoming one of the most important chronic liver diseases among children [2]. The spectrum of NAFLD ranges from simple steatosis to steatosis associated with inflammation and fibrosis (non-alcoholic steatohepatitis, NASH), which can eventually progress to liver cirrhosis [3] It has been demonstrated, that children with NAFLD may develop later in life severe liver disease with a consequent need for liver transplantation [4]. Aims of this study were i) to analyse in a large group of obese children the role of the interaction of not-genetic factors such as BMI, waist circumference (W/Hr) and insulin resistance (HOMA-IR) in exposing the association between the I148M polymorphism and ALT levels and ii) to stratify the individual risk of these children to have liver injury on the basis of this gene-environment interaction

Methods

Results

Conclusion