Original Article—Liver, Pancreas, and Biliary Tract

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 InamineAffiliated withDepartment of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences
  • , Shingo HigaAffiliated withDepartment of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences
  • , Fumie NoguchiAffiliated withDepartment of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences
  • , Shinji KondoAffiliated withDepartment of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences
  • , Katsuhisa OmagariAffiliated withDepartment of Nutrition, Faculty of Nursing and Nutrition, Siebold University of Nagasaki
  • , Hiroshi YatsuhashiAffiliated withClinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences
  • , Kazuhiro TsukamotoAffiliated withDepartment of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences Email author 
  • , Minoru NakamuraAffiliated withClinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Department of Hepatology, Nagasaki University Graduate School of Biomedical SciencesHeadquarters of PBC Research in the NHO Study Group for Liver Disease in Japan (NHOSLJ)

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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 progression Bile acid synthesis CYP7A1 PGC-1α HNF4α