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Developmental research on the novel genetic factors related to alcohol metabolism

Research Project

Project/Area Number 12470106
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Legal medicine
Research InstitutionUniversity of Tsukuba

Principal Investigator

NAKAMURA Jiro (2002)  University of Tsukuba, University of Tsukuba, Institute of Clinical medicine, Associate Professor (10110751)

原田 勝二 (2000-2001)  筑波大学, 社会医学系, 教授 (60086618)

Co-Investigator(Kenkyū-buntansha) NOMURA Fumio  University of Chiba, 医学部, Professor (80164739)
中村 二郎  筑波大学, 臨床医学系, 講師 (10110751)
Project Period (FY) 2000 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥6,600,000 (Direct Cost: ¥6,600,000)
Fiscal Year 2002: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 2001: ¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 2000: ¥2,400,000 (Direct Cost: ¥2,400,000)
KeywordsAlcohol / Metabolisms / ADH2 / ALDH2 / CYP2E1 / GSTM1 / NQO2 / Alcohol consumption / アルコール依存症 / 離脱症状 / 遺伝的リスク因子 / GSTM1遺伝子 / NQO1遺伝子 / NQO2遺伝子 / 多型性変異 / 転写制御領域 / CCKA受容体遺伝子 / CCKB受容体遺伝子 / CCK遺伝子 / 幻覚 / Promoter / Alcoholism / Association Analysis / 転写因子 / 遺伝的多型 / 人種差
Research Abstract

1) We analyzed 600 nucleotides of the promoter region in addition to exon 12 from 571 Japanese, 68 Chinese, 80 Myanmar, 60 Mongolians, and 82 North-American Caucasians using single-strand conformational change polymorphism (SSCP) analysis. A novel polymorphism at -357 with a G to A substitution was found in all the population groups, including North-American Caucasians. A total of 206 healthy male controls and 185 alcoholic male patients with the homozygous ALDH2^*1 genotype were analyzed for the polymorphism in the promoter. The A allele frequencies for alcoholics and controls were 0.24 and 0.27, respectively. A chi2 test for the entire 3×2 table indicated significant variations in the three genotypes (chi2=6.40, p<0.05).
2) NRH-quinone oxidoreductase 2 (NQO2) is involved in phase II detoxification reactions, and along with Glutathione S-transferase M1 (GSTM1) and NAD(P)H-quinone oxidoreductase 1 (NQO1) is thought to be important for detoxification of catechol o-quinones in the Central Nervous System. In this study, we investigated a possible association between polymorphisms of the GSTM1, NQO1 and NQO2 genes and alcohol withdrawal symptoms such as delirium tremens, hallucination, and seizure. A significant difference was found between alcoholic patients and controls in genotype frequency at an insertion/deletion (I/D) site in the promoter region of the NQO2 gene (p=0.0014). The frequency of the homozygous genotype for the .D allele at this locus was significantly higher in delirium tremens positive patients (p=0.0004) and in hallucination positive patients (p=0.0001), and in patients displaying both delirium tremens and hallucination (p=0.0002), than in controls. Moreover, the GSTM1 gene deletion showed significant association with alcohol seizure symptoms. Present data suggest that an I/D polymorphism in the promoter region of the NQO2 gene plays an important role in the pathogenesis of alcoholism and alcohol withdrawal symptoms.

Report

(4 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • 2000 Annual Research Report
  • Research Products

    (33 results)

All 2003 2002 2001 2000 1999 Other

All Journal Article (16 results) Publications (17 results)

  • [Journal Article] Association Analyses between Polymorphisms of the Phase II Detoxification Enzymes (GSTM1, NQO1, NQO2) and Alcohol Withdrawal Symptoms.2003

    • Author(s)
      Okubo T, Harada S, Higucbi S, Matsushita S.
    • Journal Title

      Alcohol Clin Exp Res. (in press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Journal Article] Association Analyses between Polymorphisms of the Phase II Detoxification Enzymes (GSTM1, NQO1, NQO2) and Alcohol Withdrawal Symptoms.2003

    • Author(s)
      Okubo T, Harada, S, Higuchi S, Matsushita S.
    • Journal Title

      Alcohol Clin Exp Res. (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Journal Article] lnvestigation of quantitative trait loci in the CCKAR gene with susceptibility to alcoholism.2002

    • Author(s)
      Okubo T, Harada S, Higucbi S, Matsushita S.
    • Journal Title

      Alcohol Clin Exp Res. 26(8):2S-5S.

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Journal Article] Investigation of quantitative trait loci in the CCKAR gene with susceptibility to alcoholism.2002

    • Author(s)
      Okubo T, Harada S, Higuchi S, Matsushita S.
    • Journal Title

      Alcohol Clin Exp Res. 26(8)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Journal Article] Polymorphisms of the CCK, CCKAR and CCKBR genes : an association with alcoholism study.2001

    • Author(s)
      Okubo T, Harada S.
    • Journal Title

      J Stud Alcohol ; 62(4):413-421.

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Journal Article] Polymorphism of the neuropeptide Y gene : an association study with alcohol withdrawal.2001

    • Author(s)
      Okubo T, Harada S.
    • Journal Title

      Alcohoi Clin Exp Res 25(6):59S-62S

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Journal Article] Metabolic and ethnic determinants of alcohol drinking habits and vulnerability to alcohol-related disorders.2001

    • Author(s)
      Harada, S, Agarwal DP, Nomura F, Higuchi S
    • Journal Title

      Alcohol Clin Exp Res, 25 71S-75S

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Journal Article] Polymorphism of the 5'-flanking region of the CYP2E1 gene : an association study with alcoholism.2001

    • Author(s)
      Itoga S, Harada S, Nomura F.
    • Journal Title

      Alcohol Clin Exp Res. 25(6):11S-5S

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Journal Article] Polymorphisms of the CCK, CCKAR and CCKBR genes : an association with alcoholism study.2001

    • Author(s)
      Okubo T, Harada S.
    • Journal Title

      J Stud Alcohol ; 62(4)

      Pages: 413-421

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Journal Article] Polymorphism of the neuropeptide Y gene : an association study with alcohol withdrawal.2001

    • Author(s)
      Okubo T, Harada S.
    • Journal Title

      Alcohol Clin Exp Res 25(6)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Journal Article] Metabolic and ethnic determinants of alcohol drinking habits and vulnerability to alcohol-related disorders .2001

    • Author(s)
      Harada, S, Agarwal DP, Nomura F, Higuchi S
    • Journal Title

      Alcohol Clin Exp Res 25

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Journal Article] Polymorphism of the 5'-flanking region of the CYP2E1 gene : an association study with alcoholism.2001

    • Author(s)
      Itoga S, Harada S, Nomura F.
    • Journal Title

      Alcohol Clin Exp Res. 25(6)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Journal Article] Genetic polymorphism of the CCK gene in patients with alcohol withdrawal symptoms.2000

    • Author(s)
      Okubo T, Harada S, Higuchi S, Matsushita S.
    • Journal Title

      Alcohol Clin Exp Res.; 24(4)12S-4S.

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Journal Article] Genetic polymorphism of the CCK gene in patients with alcohol withdrawal symptoms.2000

    • Author(s)
      Okubo T, Harada S, Higuchi S, Matsushita S.
    • Journal Title

      Alcohol Clin Exp Res. 24(4)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Journal Article] A novel polymorphism (-357 G/A) of the ALDH2 gene : linkage disequilibrium and an association with alcoholism.1999

    • Author(s)
      Harada S, Okubo T, Nakamura T, Fujii C, Nomura F, Higuchi S, Tsutsumi M.
    • Journal Title

      Alcohol Clin Exp Res. Jun ; 23(6)

      Pages: 958-62

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Journal Article] A novel polymorphism (-357 G/A) of the ALDH2 gene : linkage disequilibrium and an association with alcoholism.

    • Author(s)
      Harada S, Okubo T, Nakamura T, Fujii C, Nomura F, Higuchi S, Tsutsumi M.
    • Journal Title

      Alcohol Clin Exp Res. 1999 Jun;23(6):958-62

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Okubo T, Harada S, Higuchi S, Matsushita S.: "Association Analyses between Polymorphisms of the Phase II Detoxification Enzymes (GSTM1, NQO1, NQO2) and Alcohol Withdrawal Symptoms"Alcohol Clin Exp Res.. 27(in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Okubo T, Harada S, Higuchi S, Matsushfta S.: "Investigation of quantitative trait loci in the CCKAR gene with susceptibility to alcoholism"Alcohol Clin Exp Res.. 26(8). 2s-5s (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Itoga S, Nomura F, Harada S, et al.: "Tandem repeat polymorphism of the CYP2E1 gene : an association study with esophageal cancer and lung cancer"Alcohol Clin Exp Res.. 26(8). 15s-19s (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 原田勝二: "日本人のアルコール代謝酵素の遺伝的多型"最新医学. 57. 104-114 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 原田勝二: "アルコール依存症と関連するADHとALDH"分子精神医学. 2. 15-23 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Harada, S., et al.: "Metabolic and ethnic determinants of alcohol drinking habits and vulnerabilityto alcohol-related disorders"Alcohol Clin Exp Res. 25. 71-75 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Okubo T., Harada S.: "Polymorphism of the CCK,CCKAR,and CCKBR genes:An assciation study with alcoholism"J.Studies Alcohol. 25. 413-421 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 大久保武人, 原田勝二: "アルコール離脱症状に対する易罹病性と関連するCCK関連遺伝子QTLの多型"アルコールと医学生物学. 21. 113-118 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 原田勝二: "アルコール代謝酵素の分類と多型-日本人における特異性"日本アルコール薬物医学会雑誌. 36(2). 85-106 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 原田勝二: "飲酒様態に関与する遺伝子情報"日本醸造協会誌. 96(4). 210-220 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Harada,S and Agarwal D.P.: "Metabolic and Ethnic Determinants of Alcohol Drinking Habits and Vulnerability to Alcohol -Related Disorders"Alcohol Clin Exp Res,. 25.(in press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Okubo,T.,Harada,S.,Higuchi,S.: "Genetic polymorphism of the CCK gene in patients with alcohol withdrawal symptoms."Alcohol Clin Exp Res. 24. 2-4 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 原田勝二: "アルコールと人類遺伝学-ALDH2多型と飲酒量に関する遺伝生態学的研究."日ア精神誌. 7. 39-43 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Harada,S: "Genetic variability in alcohol metabolism and drinking habits in Japanese."Alcohol Clin Exp Res.. 24(5). 201-201 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 糸賀栄,野村文夫,原田勝二: "CYP2E1遺伝子5'末端上流反復配列の新たな多型と飲酒量との相関."アルコールと医学生物学. 20. 66-69 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Harada,S.,Couzigou,P.,Courtault-Labeyrie,C.: ": Polymorphism for the promoter region of the ALDH2 gene in French Caucasians and African vatives."Alcohol Clin Exp Res. 24(5). 173-173 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 原田勝二 編.: "アルコールと医学生物学-アルコール関連障害のリスク因子vol20"東洋書店,東京,. 180 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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