title: The association of PNPLA3 variants with liver enzymes in childhood obesity is driven by the interaction with abdominal fat.
abstract: OBJECTIVE
  A 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.
  
  
  METHODS
  1048 Italian obese children were investigated. Anthropometric, clinical and metabolic data were collected and the PNPLA3 I148M variant genotyped.
  
  
  RESULTS
  Children 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.
  
  
  CONCLUSIONS
  We 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.
authors.affiliation: Department of Pediatrics, Seconda Università degli Studi di Napoli, Napoli, Italy. emanuele.miraglia@unina2.it
authors.forename: Emanuele Miraglia del
authors.initials: EM
authors.lastname: Giudice
authors.forename: Anna
authors.initials: A
authors.lastname: Grandone
authors.forename: Grazia
authors.initials: G
authors.lastname: Cirillo
authors.forename: Nicola
authors.initials: N
authors.lastname: Santoro
authors.forename: Alessandra
authors.initials: A
authors.lastname: Amato
authors.forename: Carmine
authors.initials: C
authors.lastname: Brienza
authors.forename: Piera
authors.initials: P
authors.lastname: Savarese
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Marzuillo
authors.forename: Laura
authors.initials: L
authors.lastname: Perrone
mesh_terms: D050153:Abdominal Fat / Q000378:metabolism*; D000410:Alanine Transaminase / Q000378:metabolism*; D002648:Child; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008049:Lipase / Q000235:genetics*; D008099:Liver / Q000201:enzymology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009765:Obesity / Q000201:enzymology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D000410:Alanine Transaminase; D008049:Lipase; D008565:Membrane Proteins; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent