title: A common variant in the patatin-like phospholipase 3 gene (PNPLA3) is associated with fatty liver disease in obese children and adolescents.
abstract: The genetic factors associated with susceptibility to nonalcoholic fatty liver disease (NAFLD) in pediatric obesity remain largely unknown. Recently, a nonsynonymous single-nucleotide polymorphism (rs738409), in the patatin-like phospholipase 3 gene (PNPLA3) has been associated with hepatic steatosis in adults. In a multiethnic group of 85 obese youths, we genotyped the PNLPA3 single-nucleotide polymorphism, measured hepatic fat content by magnetic resonance imaging and insulin sensitivity by the insulin clamp. Because PNPLA3 might affect adipogenesis/lipogenesis, we explored the putative association with the distribution of adipose cell size and the expression of some adipogenic/lipogenic genes in a subset of subjects who underwent a subcutaneous fat biopsy. Steatosis was present in 41% of Caucasians, 23% of African Americans, and 66% of Hispanics. The frequency of PNPLA3(rs738409) G allele was 0.324 in Caucasians, 0.183 in African Americans, and 0.483 in Hispanics. The prevalence of the G allele was higher in subjects showing hepatic steatosis. Surprisingly, subjects carrying the G allele showed comparable hepatic glucose production rates, peripheral glucose disposal rate, and glycerol turnover as the CC homozygotes. Carriers of the G allele showed smaller adipocytes than those with CC genotype (P = 0.005). Although the expression of PNPLA3, PNPLA2, PPARγ2(peroxisome proliferator-activated receptor gamma 2), SREBP1c(sterol regulatory element binding protein 1c), and ACACA(acetyl coenzyme A carboxylase) was not different between genotypes, carriers of the G allele showed lower leptin (LEP)(P = 0.03) and sirtuin 1 (SIRT1) expression (P = 0.04).
  
  
  CONCLUSIONS
  A common variant of the PNPLA3 gene confers susceptibility to hepatic steatosis in obese youths without increasing the level of hepatic and peripheral insulin resistance. The rs738409 PNPLA3 G allele is associated with morphological changes in adipocyte cell size.
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Nicola
authors.initials: N
authors.lastname: Santoro
authors.forename: Romy
authors.initials: R
authors.lastname: Kursawe
authors.forename: Ebe
authors.initials: E
authors.lastname: D'Adamo
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Dykas
authors.forename: Clarence K
authors.initials: CK
authors.lastname: Zhang
authors.forename: Allen E
authors.initials: AE
authors.lastname: Bale
authors.forename: Anna M
authors.initials: AM
authors.lastname: Calí
authors.forename: Deepak
authors.initials: D
authors.lastname: Narayan
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Shaw
authors.forename: Bridget
authors.initials: B
authors.lastname: Pierpont
authors.forename: Mary
authors.initials: M
authors.lastname: Savoye
authors.forename: Derek
authors.initials: D
authors.lastname: Lartaud
authors.forename: Samuel
authors.initials: S
authors.lastname: Eldrich
authors.forename: Samuel W
authors.initials: SW
authors.lastname: Cushman
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhao
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
authors.forename: Sonia
authors.initials: S
authors.lastname: Caprio
mesh_terms: D000273:Adipose Tissue / Q000166:cytology; D000293:Adolescent; D048429:Cell Size; D002648:Child; D005234:Fatty Liver / Q000235:genetics* / Q000473:pathology; D005260:Female; D015870:Gene Expression; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008049:Lipase / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D008297:Male; D009765:Obesity / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D000217:Acyltransferases
chemical_list: D008049:Lipase; C494794:PNPLA2 protein, human; D000217:Acyltransferases
references.citation: Fed Proc. 1970 Jul-Aug;29(4):1516-21
references.pmid: 5459900
references.citation: Lancet. 2003 Sep 20;362(9388):951-7
references.pmid: 14511928
references.citation: Hepatology. 2010 Feb;51(2):679-89
references.pmid: 20041406
references.citation: J Biol Chem. 2001 Sep 7;276(36):33336-44
references.pmid: 11431482
references.citation: N Engl J Med. 2002 Apr 18;346(16):1221-31
references.pmid: 11961152
references.citation: Dig Dis Sci. 1995 Sep;40(9):2002-9
references.pmid: 7555456
references.citation: Endocrinol Metab Clin North Am. 2009 Sep;38(3):549-63
references.pmid: 19717004
references.citation: Diabetes Care. 1999 Sep;22(9):1462-70
references.pmid: 10480510
references.citation: Diabetes. 2009 Nov;58(11):2616-23
references.pmid: 19651814
references.citation: J Clin Invest. 2007 Mar;117(3):739-45
references.pmid: 17318260
references.citation: Int J Obes (Lond). 2010 Jan;34(1):190-4
references.pmid: 19844213
references.citation: Proc Natl Acad Sci U S A. 2008 Jul 15;105(28):9793-8
references.pmid: 18599449
references.citation: J Clin Endocrinol Metab. 2004 Jun;89(6):2684-9
references.pmid: 15181042
references.citation: Hepatology. 2009 Jun;49(6):1896-903
references.pmid: 19434725
references.citation: Diabetes. 2006 Mar;55(3):826-33
references.pmid: 16505250
references.citation: J Lipid Res. 2009 Oct;50(10):2111-6
references.pmid: 19738004
references.citation: Magn Reson Med. 2008 Mar;59(3):521-7
references.pmid: 18306404
references.citation: Magn Reson Imaging. 1997;15(3):287-93
references.pmid: 9201675
references.citation: Mol Cell Endocrinol. 2009 Nov 13;311(1-2):39-46
references.pmid: 19619606
references.citation: Cell Metab. 2005 Jul;2(1):55-65
references.pmid: 16054099
references.citation: Nature. 2004 Jun 17;429(6993):771-6
references.pmid: 15175761
references.citation: Diabetologia. 2009 Jun;52(6):1056-60
references.pmid: 19224197
references.citation: Pediatrics. 2006 Oct;118(4):1388-93
references.pmid: 17015527
references.citation: J Clin Endocrinol Metab. 2004 Mar;89(3):1096-101
references.pmid: 15001593
references.citation: Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17075-80
references.pmid: 17940018
references.citation: J Clin Invest. 2006 Mar;116(3):817-24
references.pmid: 16485039
references.citation: J Biol Chem. 2010 Feb 26;285(9):6706-15
references.pmid: 20034933
references.citation: Nat Genet. 2008 Dec;40(12):1461-5
references.pmid: 18820647
references.citation: Cell Metab. 2007 Jul;6(1):69-78
references.pmid: 17618857
references.citation: Am J Physiol Regul Integr Comp Physiol. 2004 Jul;287(1):R112-9
references.pmid: 15001430
references.citation: J Biol Chem. 2004 Nov 19;279(47):48968-75
references.pmid: 15364929
references.citation: Hepatology. 2010 Apr;51(4):1209-17
references.pmid: 20373368
references.citation: PLoS Comput Biol. 2009 Mar;5(3):e1000324
references.pmid: 19325873
references.citation: J Biol Chem. 2000 Mar 24;275(12):8456-60
references.pmid: 10722680
references.citation: J Hepatol. 2010 Aug;53(2):335-8
references.pmid: 20546964
references.citation: Gut. 2009 Nov;58(11):1538-44
references.pmid: 19625277
references.citation: J Biol Chem. 2004 Jul 30;279(31):32345-53
references.pmid: 15166226
references.citation: J Lipid Res. 2005 Nov;46(11):2477-87
references.pmid: 16150821
references.citation: J Cell Biochem. 2008 Dec 15;105(6):1430-6
references.pmid: 18980248
references.citation: Diabetes. 1987 Aug;36(8):914-24
references.pmid: 3297886
references.citation: Diabetologia. 2007 Aug;50(8):1707-15
references.pmid: 17549449