title: Genetic factors in the pathogenesis of cholangiocarcinoma.
abstract: BACKGROUND
  Cholangiocarcinoma (CC) is increasing in incidence, but its pathogenesis remains poorly understood. Chronic inflammation of the bile duct and cholestasis are major risk factors, but most cases in the West are sporadic. Genetic polymorphisms in biliary transporter proteins have been implicated in benign biliary disease and, in the case of progressive familial cholestasis, have been associated with childhood onset of CC. In the current study, five biologically plausible candidate genes were investigated: ABCB11 (BSEP), ABCB4 (MDR3), ABCC2 (MRP2), ATP8B1 (FIC1) and NR1H4 (FXR).
  
  
  METHODS
  DNA was collected from 172 Caucasian individuals with confirmed CC. A control cohort of healthy Caucasians was formed. Seventy-three SNPs were selected using the HapMap database to capture genetic variation around the five candidate loci. Genotyping was undertaken with a competitive PCR-based system. Confirmation of Hardy-Weinberg equilibrium and Cochran-Armitage trend testing were performed using PLINK. Haplotype frequencies were compared using haplo.stats.
  
  
  RESULTS
  All 73 SNPs were in Hardy-Weinberg equilibrium. Four SNPs in ABCB11 were associated with altered susceptibility to CC, including the V444A polymorphism, but these associations did not retain statistical significance after Bonferroni correction for multiple testing. Haplotype analysis of the genotyped SNPs in ATP8B1 identified significant differences in frequencies between cases and controls (global p value of 0.005).
  
  
  CONCLUSIONS
  Haplotypes in ATP8B1 demonstrated a significant difference between CC and control groups. There was a trend towards significant association of V444A with CC. Given the biological plausibility of polymorphisms in ABCB11 and ATP8B1 as risk modifiers for CC, further study in a validation cohort is required.
authors.affiliation: Department of Hepatology and Gastroenterology, Imperial College London, London, UK.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Wadsworth
authors.forename: Peter H
authors.initials: PH
authors.lastname: Dixon
authors.forename: Jason H
authors.initials: JH
authors.lastname: Wong
authors.forename: Michael H
authors.initials: MH
authors.lastname: Chapman
authors.forename: Siobhan C
authors.initials: SC
authors.lastname: McKay
authors.forename: Amar
authors.initials: A
authors.lastname: Sharif
authors.forename: Duncan R
authors.initials: DR
authors.lastname: Spalding
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Pereira
authors.forename: Howard C
authors.initials: HC
authors.lastname: Thomas
authors.forename: Simon D
authors.initials: SD
authors.lastname: Taylor-Robinson
authors.forename: John
authors.initials: J
authors.lastname: Whittaker
authors.forename: Catherine
authors.initials: C
authors.lastname: Williamson
authors.forename: Shahid A
authors.initials: SA
authors.lastname: Khan
mesh_terms: D001648:Bile Canaliculi / Q000473:pathology; D001660:Biliary Tract Diseases / Q000235:genetics / Q000473:pathology; D018281:Cholangiocarcinoma / Q000208:ethnology / Q000235:genetics*; D004785:Environmental Pollutants / Q000633:toxicity; D006801:Humans; D026901:Membrane Transport Proteins / Q000378:metabolism; D000089762:Multidrug Resistance-Associated Protein 2; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: C000715087:ABCC2 protein, human; D004785:Environmental Pollutants; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2