title: The 148M allele of the PNPLA3 gene is associated with indices of liver damage early in life.
abstract: OBJECTIVE
  Childhood obesity is a growing problem worldwide. Non-alcoholic fatty liver disease (NAFLD) is frequently associated with obesity in children. Recently, the PNPLA3 gene I148M (rs738409) variant was demonstrated to be strongly associated with hepatic steatosis in obese adults. In this study we add further insight into the role of PNPLA3 by exploring whether this association begins early in life in obese children or becomes manifest only in adulthood.
  
  
  METHODS
  Four hundred and seventy-five obese/overweight children and adolescents were genotyped for the I148M allele. Clinical and biochemical parameters were collected for all participants, including indices of hepatic injury, glucose tolerance and insulin resistance. Ultrasound imaging of the liver was obtained to assess the degree of steatosis in a subset of children.
  
  
  RESULTS
  Carriers of two 148M alleles had a 52% increase in circulating ALT levels compared to carriers of two 148I alleles, with individuals with one 148M allele showing a 9.5% increase (p=0.001). AST concentration was also significantly higher in carriers of two and one M alleles (17.4% and 4%, respectively, p=0.022). A total of 36% of carries of two 148M alleles showed elevated ALT, defined as >30U/L, compared to only 10% of carriers of two 148I alleles (p<0.001). Liver steatosis was more prevalent in carriers of two 148M alleles. Glucose tolerance and insulin sensitivity were similar across all three genotypes.
  
  
  CONCLUSIONS
  Our data show that the PNPLA3 gene I148M variant is associated with increased levels of ALT/AST in obese children and adolescents, suggesting that it confers genetic susceptibility to liver damage from a young age.
authors.affiliation: Endocrinology and Diabetes, Department of Medical Sciences, University of Cagliari, Cagliari, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Romeo
authors.forename: Federica
authors.initials: F
authors.lastname: Sentinelli
authors.forename: Valentina M
authors.initials: VM
authors.lastname: Cambuli
authors.forename: Michela
authors.initials: M
authors.lastname: Incani
authors.forename: Tiziana
authors.initials: T
authors.lastname: Congiu
authors.forename: Vanessa
authors.initials: V
authors.lastname: Matta
authors.forename: Sabrina
authors.initials: S
authors.lastname: Pilia
authors.forename: Isabel
authors.initials: I
authors.lastname: Huang-Doran
authors.forename: Efisio
authors.initials: E
authors.lastname: Cossu
authors.forename: Sandro
authors.initials: S
authors.lastname: Loche
authors.forename: Marco G
authors.initials: MG
authors.lastname: Baroni
mesh_terms: D000293:Adolescent; D000410:Alanine Transaminase / Q000097:blood; D001219:Aspartate Aminotransferases / Q000097:blood; D002648:Child; D015331:Cohort Studies; D005234:Fatty Liver / Q000208:ethnology / Q000235:genetics*; D005260:Female; D005787:Gene Frequency / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007558:Italy; D008049:Lipase / Q000235:genetics*; D008107:Liver Diseases / Q000208:ethnology / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009765:Obesity / Q000097:blood / Q000150:complications; D050177:Overweight / Q000097:blood / Q000150:complications; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D000410:Alanine Transaminase; D001219:Aspartate Aminotransferases; D008049:Lipase; D008565:Membrane Proteins; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent