title: A common polymorphism in the NCAN gene is associated with hepatocellular carcinoma in alcoholic liver disease.
abstract: OBJECTIVE
  The genetic background of alcoholic liver diseases and their complications are increasingly recognized. A common polymorphism in the neurocan (NCAN) gene, which is known to be expressed in neuronal tissue, has been identified as a risk factor for non-alcoholic fatty liver disease (NAFLD). We investigated if this polymorphism may also be related to alcoholic liver disease (ALD) and hepatocellular carcinoma (HCC).
  
  
  METHODS
  We analysed the distribution of the NCAN rs2228603 genotypes in 356 patients with alcoholic liver cirrhosis, 126 patients with alcoholic HCC, 382 persons with alcohol abuse without liver damage, 362 healthy controls and in 171 patients with hepatitis C virus (HCV) associated HCC. Furthermore, a validation cohort of 229 patients with alcoholic cirrhosis (83 with HCC) was analysed. The genotypes were determined by LightSNiP assays. The expression of NCAN was studied by RT-PCR and immunofluorescence microscopy.
  
  
  RESULTS
  The frequency of the NCAN rs2228603 T allele was significantly increased in patients with HCC due to ALD (15.1%) compared to alcoholic cirrhosis without HCC (9.3%), alcoholic controls (7.2%), healthy controls (7.9%), and HCV associated HCC (9.1%). This finding was confirmed in the validation cohort (15.7% vs. 6.8%, OR=2.53; 95%CI: 1.36-4.68; p=0.0025) and by multivariate analysis (OR=1.840; 95%CI: 1.22-2.78; p=0.004 for carriage of the rs2228603 T allele). In addition, we identified and localised NCAN expression in human liver.
  
  
  CONCLUSIONS
  NCAN is not only expressed in neuronal tissue, but also in the liver. Its rs2228603 polymorphism is a risk factor for HCC in ALD, but not in HCV infection.
authors.affiliation: Department of Internal Medicine I, University of Bonn, Germany.
authors.forename: Hans Dieter
authors.initials: HD
authors.lastname: Nischalke
authors.affiliation: Department of Internal Medicine I, University of Bonn, Germany; German Center for Infection Research, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Lutz
authors.affiliation: Department of Internal Medicine I, University of Bonn, Germany; German Center for Infection Research, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Krämer
authors.affiliation: Department of Internal Medicine I, University of Bonn, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Söhne
authors.affiliation: Department of Gastroenterology, University Hospital Leipzig, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Müller
authors.affiliation: Department of Gastroenterology, University Hospital Leipzig, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Rosendahl
authors.affiliation: Department of Gastroenterology, University Hospital Leipzig, Germany.
authors.forename: Janett
authors.initials: J
authors.lastname: Fischer
authors.affiliation: Department of Gastroenterology, University Hospital Leipzig, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Berg
authors.affiliation: Department of Pathology, University Hospital Bonn, Germany.
authors.forename: Kanishka
authors.initials: K
authors.lastname: Hittatiya
authors.affiliation: Department of Pathology, University Hospital Bonn, Germany.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Fischer
authors.affiliation: Psychiatric Hospital Meiringen, Switzerland; Psychiatric Hospital, University of Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Soyka
authors.affiliation: Hepatology Unit, Klinik Beau-Site, Department of Visceral Surgery and Medicine Inselspital, University of Bern, Switzerland.
authors.forename: Nasser
authors.initials: N
authors.lastname: Semmo
authors.affiliation: Department of Internal Medicine I, University of Bonn, Germany; German Center for Infection Research, Germany.
authors.forename: Jacob
authors.initials: J
authors.lastname: Nattermann
authors.affiliation: Department of Internal Medicine I, University of Bonn, Germany.
authors.forename: Tilman
authors.initials: T
authors.lastname: Sauerbruch
authors.affiliation: Department of Internal Medicine I, University of Bonn, Germany; German Center for Infection Research, Germany.
authors.forename: Christian P
authors.initials: CP
authors.lastname: Strassburg
authors.affiliation: Hepatology Unit, Klinik Beau-Site, Department of Visceral Surgery and Medicine Inselspital, University of Bern, Switzerland.
authors.forename: Felix
authors.initials: F
authors.lastname: Stickel
authors.affiliation: Department of Internal Medicine I, University of Bonn, Germany; German Center for Infection Research, Germany. Electronic address: ulrich.spengler@ukb.uni-bonn.de.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Spengler
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000437:Alcoholism / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000235:genetics*; D016022:Case-Control Studies; D002460:Cell Line; D011508:Chondroitin Sulfate Proteoglycans / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D056945:Hep G2 Cells; D019698:Hepatitis C, Chronic / Q000150:complications / Q000235:genetics; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics*; D008104:Liver Cirrhosis, Alcoholic / Q000235:genetics; D008108:Liver Diseases, Alcoholic / Q000150:complications* / Q000235:genetics*; D008113:Liver Neoplasms / Q000209:etiology* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D058580:Neurocan; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D055815:Young Adult
chemical_list: D011508:Chondroitin Sulfate Proteoglycans; D037181:Lectins, C-Type; D009419:Nerve Tissue Proteins; D058580:Neurocan; D012333:RNA, Messenger; C076817:NCAN protein, human
keywords: Alcohol; HCC; Liver cirrhosis; NCAN; Neurocan; Polymorphism; SNP; rs2228603