title: Genome-wide analysis of hepatic lipid content in extreme obesity.
abstract: OBJECTIVE
  Individuals with type 2 diabetes have an increased risk of developing non-alcoholic fatty liver disease (NAFLD), and NAFLD patients are also at greater risk for developing type 2 diabetes. Although the relationship between type 2 diabetes and NAFLD is highly interconnected, the pathogenic mechanisms linking the two diseases are poorly understood. The goal of this study was to identify genetic determinants of hepatic lipid accumulation through association analysis using histological phenotypes in obese individuals.
  
  
  METHODS
  Using the Illumina HumanOmniExpress BeadChip assay, we genotyped 2,300 individuals on whom liver biopsy data were available.
  
  
  RESULTS
  We analyzed total bilirubin levels, which are linked to fatty liver in severe obesity, and observed the strongest evidence for association with rs4148325 in UGT1A (P < 5.0 × 10(-93)), replicating previous findings. We assessed hepatic fat level and found strong evidence for association with rs4823173, rs2896019, and rs2281135, all located in PNPLA3 and rs10401969 in SUGP1. Analysis of liver transcript levels of 20 genes residing at the SUGP1/NCAN locus identified a 1.6-fold change in the expression of the LPAR2 gene in fatty liver. We also observed suggestive evidence for association between low-grade fat accumulation and rs10859525 and rs1294908, located upstream from SOCS2 and RAMP3, respectively. SOCS2 was differentially expressed between fatty and normal liver.
  
  
  CONCLUSIONS
  These results replicate findings for several hepatic phenotypes in the setting of extreme obesity and implicate new loci that may play a role in the pathophysiology of hepatic lipid accumulation.
authors.affiliation: Diabetes, Cardiovascular and Metabolic Diseases Division, Translational Genomics Research Institute, 445 North Fifth Street, Phoenix, AZ, 85004, USA, jdistefano@tgen.org.
authors.forename: Johanna K
authors.initials: JK
authors.lastname: DiStefano
authors.forename: Christopher
authors.initials: C
authors.lastname: Kingsley
authors.forename: G
authors.initials: G
authors.lastname: Craig Wood
authors.forename: Xin
authors.initials: X
authors.lastname: Chu
authors.forename: George
authors.initials: G
authors.lastname: Argyropoulos
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Still
authors.forename: Stefania Cotta
authors.initials: SC
authors.lastname: Doné
authors.forename: Christophe
authors.initials: C
authors.lastname: Legendre
authors.forename: Waibhav
authors.initials: W
authors.lastname: Tembe
authors.forename: Glenn S
authors.initials: GS
authors.lastname: Gerhard
mesh_terms: D000328:Adult; D001663:Bilirubin / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology / Q000378:metabolism; D009765:Obesity / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D058264:Receptor Activity-Modifying Protein 3 / Q000235:genetics; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics
chemical_list: C545504:RAMP3 protein, human; D058264:Receptor Activity-Modifying Protein 3; C106643:SOCS2 protein, human; D050826:Suppressor of Cytokine Signaling Proteins; D001663:Bilirubin