title: Mapping of a disease susceptibility locus in the HLA region for Primary Biliary Cirrhosis in Japan.
abstract: OBJECTIVE
  Primary biliary cirrhosis (PBC) is a chronic progressive cholestatic disease of unknown pathogenesis. However, several reports have demonstrated the involvement of genetic backgrounds in this syndrome. The aim of this study is to examine the genetic disequilibrium in the HLA region in Japanese patients using six microsatellite markers.
  
  
  METHODS
  Genomic DNAs were obtained from 73 patients with PBC (patient cohort) and 186 healthy volunteers (control cohort). Genetic polymorphisms at six microsatellite markers (D6S1568, DQ.CAR, D6S273, TNF-d, C1-2-A, C3-2-11) were determined using fluorescence-labeled polymerase chain reaction (PCR) genetic analyzer. Allele frequencies were estimated by direct counting and the genotypic differentiation test was performed by the Markov chain method using Genepop software.
  
  
  RESULTS
  Among these six microsatellite markers, four markers in the patients significantly (P < 0.05) deviated from the Hardy-Weinberg equilibrium: DQ.CAR (P = 0.0278), D6S273 (P = 0.0168), TNF-d (P = 0.0089) and C1-2-A (P = 0.0005). Genotypic differentiation test between the patients and controls demonstrated that DQ.CAR (P = 0.0111), TNF-d (P = 0.0051) and C1-2-A (P = 0.0371) were significant. Finally, allelic association test revealed before correction for multiple testing demonstrated allele125 of TNF-d (P = 0.00065, Pc = 0.0052) and allele246 of C1-2-A (P = 0.0026 Pc = 0.033) had significant association after Bonferroni's correction.
  
  
  CONCLUSIONS
  Disequilibrium mapping using microsatellite markers was a useful method to narrow a disease susceptibility locus. The possible susceptibility gene in the HLA region is thought to be localized around or in the TNF gene. Further studies seem feasible using more closely distributed microsatellite markers or single nucleotide polymorphisms (SNPs) to narrow the susceptibility locus in PBC in Japanese populations.
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Kaichiro
authors.initials: K
authors.lastname: Yahagi
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Ueno
authors.forename: Eiki
authors.initials: E
authors.lastname: Nomura
authors.forename: Koji
authors.initials: K
authors.lastname: Fukushima
authors.forename: Yuki
authors.initials: Y
authors.lastname: Moritoki
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kogure
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kojima
authors.forename: Kenichi
authors.initials: K
authors.lastname: Negoro
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Kinouchi
authors.forename: Tooru
authors.initials: T
authors.lastname: Shimosegawa