Association of genes involved in bile acid synthesis with the progression of primary biliary cirrhosis in Japanese patients
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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.
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.
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.
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.
KeywordsPBC progression Bile acid synthesis CYP7A1 PGC-1α HNF4α
- 6.Nakamura M, Yasunami M, Kondo H, Horie H, Aiba Y, Komori A, et al. Analysis of HLA-DRB1 polymorphisms in Japanese patients with primary biliary cirrhosis (PBC): the HLA-DRB1polymorphism determines the relative risk of antinuclear antibodies for disease progression in PBC. Hepatol Res. 2010;40:494–504.PubMedCrossRefGoogle Scholar
- 20.Takeyama Y, Kanegae K, Inomata S, Takata K, Tanaka T, Ueda S, et al. Sustained upregulation of sodium taurocholate cotransporting polypeptide and bile salt export pump and downregulation of cholesterol 7α-hydroxylase in the liver of patients with end-stage primary biliary cirrhosis. Med Mol Morphol. 2010;43:134–8.PubMedCrossRefGoogle Scholar
- 21.Zollner G, Wagner M, Moustafa T, Fickert P, Silbert D, Gumhold J, et al. Coordinated induction of bile acid detoxification and alternative elimination in mice: role of FXR-regulated organic solute transporter-alpha/beta in the adaptive response to bile acids. Am J Physiol Gastrointest Liver Physiol. 2006;290:G923–32.PubMedCrossRefGoogle Scholar
- 26.Choi Y-S, Hong J-M, Lim S, Ko KS, Pak YK. Impaired coactivator activity of the Gly482 variant of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) on mitochondrial transcription factor A (Tfam) promoter. Biochem Biophys Res Commun. 2006;344:708–12.PubMedCrossRefGoogle Scholar
- 29.De Castro-Orós I, Pampín S, Cofán M, Mozas P, Pintó X, Salas-Salvadó J, et al. Promoter variant -204A>C of the cholesterol 7α -hydroxylase gene: association with response to plant sterols in humans and increased transcriptional activity in transfected HepG2 cells. Clin Nutr. 2011;30:239–46.PubMedCrossRefGoogle Scholar