title: Genetic variation at NCAN locus is associated with inflammation and fibrosis in non-alcoholic fatty liver disease in morbid obesity.
abstract: OBJECTIVE
  Obesity-associated non-alcoholic fatty liver disease (NAFLD) may cause liver dysfunction and failure. In a previously reported genome-wide association meta-analysis, single nucleotide polymorphisms (SNPs) near PNPLA3, NCAN, GCKR, LYPLAL1 and PPP1R3B were associated with NAFLD and with distinctive serum lipid profiles. The present study examined the relevance of these variants to NAFLD in extreme obesity.
  
  
  METHODS
  In 1,092 bariatric surgery patients, the candidate SNPs were genotyped and association analyses with liver histology and serum lipids were performed.
  
  
  RESULTS
  We replicated the association of hepatosteatosis with PNPLA3 rs738409[G] and with NCAN rs2228603[T]. We also replicated the association of rs2228603[T] with hepatic inflammation and fibrosis. rs2228603[T] was associated with lower serum low-density lipoprotein, total cholesterol and triglycerides. After stratification by the presence or absence of NAFLD, these associations were present predominantly in the subgroup with NAFLD.
  
  
  CONCLUSIONS
  NCAN rs2228603[T] is a risk factor for liver inflammation and fibrosis, suggesting that this locus is responsible for progression from steatosis to steatohepatitis. In this bariatric cohort, rs2228603[T] was associated with low serum lipids only in patients with NAFLD. This supports a NAFLD model in which the liver may sequester triglycerides as a result of either increased triglyceride uptake and/or decreased lipolysis.
authors.affiliation: Division of Gastroenterology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Alexis
authors.initials: A
authors.lastname: Gorden
authors.forename: Rongze
authors.initials: R
authors.lastname: Yang
authors.forename: Laura M
authors.initials: LM
authors.lastname: Yerges-Armstrong
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Ryan
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Speliotes
authors.forename: Ingrid B
authors.initials: IB
authors.lastname: Borecki
authors.forename: Tamara B
authors.initials: TB
authors.lastname: Harris
authors.forename: Xin
authors.initials: X
authors.lastname: Chu
authors.forename: G Craig
authors.initials: GC
authors.lastname: Wood
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Still
authors.forename: Alan R
authors.initials: AR
authors.lastname: Shuldiner
authors.forename: Glenn S
authors.initials: GS
authors.lastname: Gerhard
mesh_terms: D000328:Adult; D002784:Cholesterol / Q000097:blood; D011508:Chondroitin Sulfate Proteoglycans / Q000097:blood / Q000235:genetics*; D005234:Fatty Liver / Q000097:blood / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D037181:Lectins, C-Type / Q000097:blood / Q000235:genetics*; D008103:Liver Cirrhosis / Q000097:blood / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000097:blood / Q000235:genetics*; D058580:Neurocan; D065626:Non-alcoholic Fatty Liver Disease; D009767:Obesity, Morbid / Q000097:blood / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D014280:Triglycerides / Q000097:blood
chemical_list: D011508:Chondroitin Sulfate Proteoglycans; D037181:Lectins, C-Type; D009419:Nerve Tissue Proteins; D058580:Neurocan; D014280:Triglycerides; C076817:NCAN protein, human; D002784:Cholesterol