Journal of Gastroenterology

, Volume 48, Issue 10, pp 1160–1170

Association of genes involved in bile acid synthesis with the progression of primary biliary cirrhosis in Japanese patients

  • Tatsuo Inamine
  • Shingo Higa
  • Fumie Noguchi
  • Shinji Kondo
  • Katsuhisa Omagari
  • Hiroshi Yatsuhashi
  • Kazuhiro Tsukamoto
  • Minoru Nakamura
Original Article—Liver, Pancreas, and Biliary Tract

DOI: 10.1007/s00535-012-0730-9

Cite this article as:
Inamine, T., Higa, S., Noguchi, F. et al. J Gastroenterol (2013) 48: 1160. doi:10.1007/s00535-012-0730-9

Abstract

Background

Patients with primary biliary cirrhosis (PBC) exhibit a variety of clinical manifestations and patterns of disease progression. The aim of this study was to identify genetic determinants of PBC progression.

Methods

A total of 52 tag single nucleotide polymorphisms (SNPs) of 11 candidate genes involved in regulating bile acid synthesis were analyzed by polymerase chain reaction (PCR)-restriction fragment length polymorphism, -high resolution melting curve analysis, or -direct DNA sequencing in 315 Japanese patients with PBC.

Results

In this study, four tag SNPs of CYP7A1 (rs1457043, rs8192870, rs3808607, and rs3824260), two tag SNPs of HNF4A (rs6017340 and 6031587), and one SNP of PPARGC1A (rs8192678) showed a significant association with PBC progression. In addition, a dual luciferase assay revealed that the polymorphism of rs3808607 in CYP7A1 altered the expression of CYP7A1 in HepG2. Specifically, the CYP7A1 promoter carrying the risk G allele for PBC progression induced higher expression of CYP7A1 under both the normal and cholestatic conditions in vitro as compared to another promoter carrying the non-risk T allele.

Conclusion

These results suggested that the genetic variants of CYP7A1 and its transcriptional activators (HNF4A and PPARGC1A) may activate bile acid synthesis, resulting in the accumulation of bile acids in hepatocytes and eventually leading to the predisposition to PBC progression. Thus, the regulation of CYP7A1 expression may represent an attractive therapeutic target for cholestatic liver diseases including PBC.

Keywords

PBC progressionBile acid synthesisCYP7A1PGC-1αHNF4α

Supplementary material

535_2012_730_MOESM1_ESM.doc (171 kb)
Supplementary material 1 (DOC 171 kb)

Copyright information

© Springer Japan 2012

Authors and Affiliations

  • Tatsuo Inamine
    • 1
  • Shingo Higa
    • 1
  • Fumie Noguchi
    • 1
  • Shinji Kondo
    • 1
  • Katsuhisa Omagari
    • 2
  • Hiroshi Yatsuhashi
    • 3
  • Kazuhiro Tsukamoto
    • 1
  • Minoru Nakamura
    • 3
    • 4
  1. 1.Department of PharmacotherapeuticsNagasaki University Graduate School of Biomedical SciencesNagasakiJapan
  2. 2.Department of Nutrition, Faculty of Nursing and NutritionSiebold University of NagasakiNagasakiJapan
  3. 3.Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Department of HepatologyNagasaki University Graduate School of Biomedical SciencesNagasakiJapan
  4. 4.Headquarters of PBC Research in the NHO Study Group for Liver Disease in Japan (NHOSLJ)NagasakiJapan