title: Interactions of allelic variance of PNPLA3 with nongenetic factors in predicting nonalcoholic steatohepatitis and nonhepatic complications of severe obesity.
abstract: OBJECTIVE
  Allelic variation (rs738409C→G) in adiponutrin (patatin-like phospholipase domain-containing protein 3, PNPLA3) has been associated with hepatic steatosis and liver fibrosis. The physiologic impact of the PNPLA3 G allele may be exacerbated in patients with severe obesity. In this study, we investigated the interactions of PNPLA3 rs738409 with a broad panel of metabolic and histologic characteristics of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH) in patients with medically complicated obesity.
  
  
  METHODS
  Consecutive patients undergoing bariatric surgery were selected for a prospective study. They underwent extensive laboratory and histologic (liver biopsy) assessment, as well as evaluation of rs738409 polymorphism by TaqMan assay.
  
  
  RESULTS
  Only 12 (8.3%) of the 144 patients had normal liver histology, with 72 (50%) NASH, of whom 15 (10.4% of total patients) had fibrosis stage 2-3. PNPLA3 GG genotype correlated positively (P < 0.05) with serum levels of alanine aminotransferase (ALT), asparate aminotransferase (AST), glucose, fibrinogen, and insulin-dependent diabetes mellitus, homeostasis model assessment-insulin resistance, and presence of NASH. Multivariate analysis indicated that PNPLA3 rs738409 G versus C allele remained an (independent) risk factor for NASH, in addition to CK-18 >145 IU/l, glucose >100 mg/dl, and C-reactive protein (CRP) >0.8 mg/dl. The probability of NASH increased from 9% (no risk factor) to 82% if all four risk factors were present.
  
  
  CONCLUSIONS
  In this cohort of patients with medically complicated obesity, PNPLA3 rs738409 G allelic expression is associated with hepatic (NASH) and nonhepatic complications of obesity, such as insulin resistance. These novel findings may be related to a greater impact of PNPLA3 variant in magnitude and scope in patients with severe obesity than in less obese populations. Further studies are needed to characterize the nature of these associations.
authors: Division of Gastroenterology and Hepatology, Medical Spectrum Twente, Enschede, The Netherlands; Liver Transplantation, Mayo Clinic, Rochester, Minnesota, USA.
authors: M M J
authors: MM
authors: Guichelaar
authors: S
authors: S
authors: Gawrieh
authors: M
authors: M
authors: Olivier
authors: K
authors: K
authors: Viker
authors: A
authors: A
authors: Krishnan
authors: S
authors: S
authors: Sanderson
authors: M
authors: M
authors: Malinchoc
authors: K D
authors: KD
authors: Watt
authors: J M
authors: JM
authors: Swain
authors: M
authors: M
authors: Sarr
authors: M R
authors: MR
authors: Charlton
mesh_terms: D000328:Adult; D000483:Alleles; D001786:Blood Glucose / Q000378:metabolism; D002097:C-Reactive Protein / Q000235:genetics / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics; D005234:Fatty Liver / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005340:Fibrinogen / Q000378:metabolism; D005355:Fibrosis; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D008049:Lipase / Q000235:genetics*; D008099:Liver / Q000201:enzymology / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D015999:Multivariate Analysis; D065626:Non-alcoholic Fatty Liver Disease; D009767:Obesity, Morbid / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D011446:Prospective Studies; D012307:Risk Factors; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D001786:Blood Glucose; D002097:C-Reactive Protein; D005340:Fibrinogen; D008049:Lipase; D008565:Membrane Proteins; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent