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

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
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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.

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Acknowledgments

This study was supported by a Grant-in-Aid for Clinical Research from the National Hospital organization to Minoru Nakamura, by a Grant-in-Aid for Scientific Research from the Japan Society for the promotion of Science to Minoru Nakamura (#20590800, #23591006) and to Katsuhisa Omagari (#20590545), by the President’s Discretionary Fund of Nagasaki University, Japan to Kazuhiro Tsukamoto, and by a research grant from the Non Profit Organization Aimed to Support Community Medicine Research in Nagasaki, Japan to Kazuhiro Tsukamoto. We thank Drs. Hiromi Ishibashi, Atsumasa Komori, Seigo Abiru, Shinya Nagaoka (NHO Nagasaki Medical Center); Makoto Nakamuta, Nobuyoshi Fukushima (NHO Kyushu Medical Center); Hajime Ota (NHO Kanazawa Medical Center); Tatsuji Komatsu (NHO Yokohama Medical Center); Jinya Ishida (NHO Nishisaitama Hospital), Hirotsugu Kouno (NHO Kure Medical Center); Michiyasu Yagura (NHO Tokyo Hospital); Masakazu Kobayashi (NHO Matsumoto Medical Center); Toyokichi Muro (NHO Oita Medical Center); Naohiko Masaki (National Center for Global Health and Medicine); Keiichi Hirata (NHO National Disaster Medical Center); Yukio Watanabe (NHO Sagamihara Hospital); Masaaki Shimada (NHO Nagoya Medical Center); Toshiki Komeda (NHO Kyoto Medical Center); Kazuhiro Sugi (NHO Kumamoto Medical Center); Eiichi Takesaki (NHO Higashihiroshima Medical Center); Yukio Ohara (NHO Hokkaido Medical Center); Hiroshi Mano (NHO Sendai Medical Center); Haruhiro Yamashita (NHO Okayama Medical Center); Michiaki Koga (NHO Ureshino Medical Center); Masahiko Takahashi (NHO Tokyo Medical Center); Tetsuo Yamamoto (NHO Yonago Medical Center); Fujio Makita (NHO Nishigunma Hospital); Hideo Nishimura (NHO Asahikawa Medical Center); Hitoshi Takagi (NHO Takasaki General Medical Center); Noboru Hirashima (NHO Higashinagoya Hospital); and Kaname Yoshizawa (NHO Shinshu Ueda Medical Center) for obtaining informed consents and collecting serum and DNA samples from PBC patients.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, 1-14 Bunkyo-machi, Nagasaki, 852-8521, Japan

    Tatsuo Inamine, Shingo Higa, Fumie Noguchi, Shinji Kondo & Kazuhiro Tsukamoto

  2. Department of Nutrition, Faculty of Nursing and Nutrition, Siebold University of Nagasaki, 1-1-1 Manabino, Nagasaki, 851-2195, Japan

    Katsuhisa Omagari

  3. Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, 2-1001-1 Kubara, Nagasaki, 856-8562, Japan

    Hiroshi Yatsuhashi & Minoru Nakamura

  4. Headquarters of PBC Research in the NHO Study Group for Liver Disease in Japan (NHOSLJ), Nagasaki, Japan

    Minoru Nakamura

Authors
  1. Tatsuo Inamine
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  2. Shingo Higa
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  3. Fumie Noguchi
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  4. Shinji Kondo
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  5. Katsuhisa Omagari
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  6. Hiroshi Yatsuhashi
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  7. Kazuhiro Tsukamoto
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  8. Minoru Nakamura
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Corresponding author

Correspondence to Kazuhiro Tsukamoto.

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Inamine, T., Higa, S., Noguchi, F. et al. Association of genes involved in bile acid synthesis with the progression of primary biliary cirrhosis in Japanese patients. J Gastroenterol 48, 1160–1170 (2013). https://doi.org/10.1007/s00535-012-0730-9

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  • DOI: https://doi.org/10.1007/s00535-012-0730-9

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