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Genetic polymorphisms of OCT-1 confer susceptibility to severe progression of primary biliary cirrhosis in Japanese patients

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

Background

To identify the genetic factors involved in the pathogenesis of primary biliary cirrhosis (PBC), we focused on the organic cation transporter 1 (OCT1/SLC22A1), which is closely associated with phosphatidylcholine synthesis in hepatocytes.

Methods

We selected four (rs683369, rs2282143, rs622342 and rs1443844) OCT-1 single nucleotide polymorphisms (SNPs), and genotyped these SNPs using the TaqMan probe method in 275 Japanese PBC patients and 194 gender-matched, healthy volunteers as controls.

Results

The Chi-square test revealed that the rs683369 variant allele (G) was associated with insusceptibility to PBC development [P = 0.009, odds ratio (OR) 0.60, 95 % confidence interval (CI) 0.40–0.88] in an allele model, and that the rs683369 variant allele (G) was associated with jaundice-type progression in a minor allele dominant genotype model (P = 0.032, OR 3.10, 95 % CI 1.05–9.14). The OCT-1 rs2282143 variant (T) and rs622342 variant (C) were also associated with jaundice-type progression in a minor allele recessive genotype model (P = 0.0002, OR 10.58, 95 % CI 2.36–47.54, and P = 0.006, OR 7.84, 95 % CI 1.39–44.36, respectively). Furthermore, the association of OCT-1 rs683369 and rs622342 with susceptibility to jaundice-type progression was confirmed by a replication study with a distinct set of PBC patients who underwent liver transplantation.

Conclusions

The present study is the first report on the association of OCT-1 genetic polymorphisms with the overall development and jaundice-type progression of PBC.

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Acknowledgments

This study was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (#20590800, #23591006) to Minoru Nakamura; by a Grant-in Aid for Clinical Research from the National Hospital Organization to Minoru Nakamura; and by the Research Program of Intractable Disease provided by the Ministry of Health, Labor, and Welfare of Japan to Hiromi Ishibashi. We thank Drs. Seigo Abiru, Shinya Nagaoka (NHO Nagasaki 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 Higashi-Hiroshima 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 consent and collecting serum and DNA samples from PBC patients.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Pharmacy, Clinical Research Institute, National Hospital Organization (NHO) Kyushu Medical Center, 1-8-1 Jigyouhama, Fukuoka, 810-8563, Japan

    Yuki Ohishi, Naoko Ishikawa, Ohki Saitoh & Takashi Nishino

  2. Department of Gastroenterology, Clinical Research Institute, National Hospital Organization (NHO) Kyushu Medical Center, 1-8-1 Jigyouhama, Fukuoka, 810-8563, Japan

    Makoto Nakamuta, Nobuyoshi Fukushima, Motoyuki Kohjima, Tsuyoshi Yoshimoto & Kunitaka Fukuizumi

  3. Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, 856-8562, Japan

    Hitomi Nakamura, Yoshihiro Aiba, Atsumasa Komori, Kiyoshi Migita, Hiroshi Yatsuhashi, Hiromi Ishibashi & Minoru Nakamura

  4. Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, 2-1001-1 Kubara, Omura, Nagasaki, 856-8562, Japan

    Atsumasa Komori, Kiyoshi Migita, Hiroshi Yatsuhashi, Hiromi Ishibashi & Minoru Nakamura

  5. Department of Pharmaceutical and Health Care Management, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, 814-0180, Japan

    Makoto Ishibashi

  6. Department of Surgery and Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, 812-8582, Japan

    Ken Shirabe, Akinobu Taketomi & Yoshihiko Maehara

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

    Minoru Nakamura

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  1. Yuki Ohishi
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  2. Makoto Nakamuta
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  3. Naoko Ishikawa
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  4. Ohki Saitoh
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  5. Hitomi Nakamura
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  6. Yoshihiro Aiba
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  7. Atsumasa Komori
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  8. Kiyoshi Migita
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  9. Hiroshi Yatsuhashi
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  10. Nobuyoshi Fukushima
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  11. Motoyuki Kohjima
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  12. Tsuyoshi Yoshimoto
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  13. Kunitaka Fukuizumi
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  14. Makoto Ishibashi
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  17. Akinobu Taketomi
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  18. Yoshihiko Maehara
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  19. Hiromi Ishibashi
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  20. Minoru Nakamura
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PBC Study Group of NHOSLJ

Corresponding author

Correspondence to Minoru Nakamura.

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Ohishi, Y., Nakamuta, M., Ishikawa, N. et al. Genetic polymorphisms of OCT-1 confer susceptibility to severe progression of primary biliary cirrhosis in Japanese patients. J Gastroenterol 49, 332–342 (2014). https://doi.org/10.1007/s00535-013-0795-0

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  • DOI: https://doi.org/10.1007/s00535-013-0795-0

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