The role of CREB gene polymorphisms in the individual differences in sensitivity to addictive substances and vulnerability to dependence

• Project/Area Number: 24790544
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Applied pharmacology
• Research Institution: Tokyo Metropolitan Institute of Medical Science
• Principal Investigator: NISHIZAWA Daisuke 公益財団法人東京都医学総合研究所, 精神行動医学研究分野, 主任研究員 (80450584)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2013: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 薬物依存 / 薬物感受性 / 薬物感受性・依存症脆弱性個人差の遺伝要因 / 遺伝子多型 / サイクリックAMP応答配列結合タンパク質 / 薬剤感受性

Outline of Final Research Achievements

In association analyses for single nucleotide polymorphisms (SNPs) in and around the CREB3, CREB5, and ATF2 (CREB2) gene regions, only rs7583431 SNP flanking the ATF2 gene was significantly associated with the effect of opioid analgesic, fentanyl.
In additional association analyses, the C allele of the rs2952768 SNP, flanking the CREB1 gene, was associated with more analgesic requirements in patients who underwent abdominal surgery, just as observed in subjects who were scheduled to undergo cosmetic orthognathic surgery. Moreover, carriers of the C allele in this SNP exhibited less vulnerability to severe drug dependence in patients with methamphetamine dependence, alcohol dependence, and eating disorders and a lower “Reward Dependence” score on a personality questionnaire and higher Intelligence Quotient (IQ) score in two independent cohorts of healthy subjects. Furthermore, the C/C genotype of this SNP was significantly associated with the elevated mRNA expression of CREB1 gene.

Research Products

• [Journal Article] Prediction formulas for individual opioid analgesic requirements based on genetic polymorphism analyses. (2015)
  • Author(s): Yoshida K, Nishizawa D, Ichinomiya T, Ichinohe T, Hayashida M, Fukuda K, Ikeda K
  • Journal Title: PLoS ONE Volume: 10 Issue: 1 Pages: e0116885-e0116885
  • DOI: 10.1371/journal.pone.0116885
  • Peer Reviewed / Open Access
• [Journal Article] Haplotypes of P2RX7 gene polymorphisms are associated with both cold pain sensitivity and analgesic effect of fentanyl. (2014)
  • Author(s): Ide S, Nishizawa D, Fukuda K, Kasai S, Hasegawa J, Hayashida M, Minami M, Ikeda K.
  • Journal Title: Mol Pain Volume: 10 Pages: 75-75
  • DOI: 10.1186/1744-8069-10-75
  • NAID: 120005549601
  • Peer Reviewed / Open Access
• [Journal Article] Association Between <i>KCNJ6</i> (<i>GIRK2</i>) Gene Polymorphism rs2835859 and Post-operative Analgesia, Pain Sensitivity, and Nicotine Dependence (2014)
  • Author(s): Nishizawa D, Fukuda K, Kasai S, Ogai Y, Hasegawa J, Sato N, Yamada H, Tanioka F, Sugimura H, Hayashida M, Ikeda K.
  • Journal Title: Journal of Pharmacological Sciences Volume: 126 Issue: 3 Pages: 253-263
  • DOI: 10.1254/jphs.14189FP
  • NAID: 130004700283
  • ISSN: 1347-8613, 1347-8648
  • Peer Reviewed / Open Access
• [Journal Article] 痛みと遺伝子多型 (2014)
  • Author(s): 西澤大輔, 池田和隆
  • Journal Title: 痛みのマネジメントupdate－基礎知識から緩和ケアまで－日本医師会雑誌 Volume: 143
• [Journal Article] 多様な依存性物質の作用に共通して影響する遺伝子多型 (2014)
  • Author(s): 西澤大輔, 池田和隆
  • Journal Title: 日本アルコール・薬物医学会雑誌 Volume: 49 Pages: 83-91
  • NAID: 40022402939
  • Peer Reviewed
• [Journal Article] Genome-wide association study identifies a potent locus associated with human opioid sensitivity. (2014)
  • Author(s): Nishizawa D, Fukuda K, Kasai S, Hasegawa J, Aoki Y, Nishi A, Saita N, Koukita Y, Nagashima M, Katoh R, Satoh Y, Tagami M, Higuchi S, Ujike H, Ozaki N, Inada T, Iwata N, Sora I, Iyo M, Kondo N, Won MJ, Naruse N, Uehara-Aoyama K, Itokawa M, Koga M, Arinami T, Kaneko Y, Hayashida M, Ikeda K.
  • Journal Title: Mol Psychiatry Volume: 19(1) Issue: 1 Pages: 55-62
  • DOI: 10.1038/mp.2012.164
  • Peer Reviewed
• [Journal Article] Association between genetic polymorphisms in Cav2.3 (R-type) Ca2+ channels and fentanyl sensitivity in patients undergoing painful cosmetic surgery (2013)
  • Author(s): Ide S, Nishizawa D, Fukuda K, Kasai S, Hasegawa J, Hayashida M, Minami M, Ikeda K
  • Journal Title: PLoS ONE Volume: 8 Issue: 8 Pages: e70694-e70694
  • DOI: 10.1371/journal.pone.0070694
  • NAID: 120005365905
  • Peer Reviewed
• [Journal Article] 様々な依存性物質の感受性に共通して関連する遺伝子多型 (2013)
  • Author(s): 西澤大輔, 池田和隆
  • Journal Title: 日本神経精神薬理学雑誌 Volume: 33 Pages: 205-209
• [Presentation] Genome-wide association study of sensory disturbances in the inferior alveolar nerve after bilateral sagittal split ramus osteotomy (2014)
  • Author(s): Nishizawa D, Kobayashi D, Takasaki Y, Kasai S, Aoki Y, Hasegawa J, Kakizawa T, Ikeda K, Fukuda K
  • Organizer: The American Society of Human Genetics 64th Annual Meeting
  • Place of Presentation: San Diego, USA
  • Year and Date: 2014-10-19
• [Presentation] ゲノムワイド関連解析によるオレキシン2受容体遺伝子多型Val308Ileとニコチン依存との関連の同定 (2014)
  • Author(s): 西澤大輔, 笠井慎也, 佐藤直美, 谷岡書彦, 長島誠, 氏家寛, 橋本亮太, 田中雅嗣, 椙村春彦, 池田和隆
  • Organizer: 平成26年度アルコール・薬物依存関連学会合同学術総会
  • Place of Presentation: パシフィコ横浜, 横浜
  • Year and Date: 2014-10-03
• [Presentation] PCLO SNP rs13438494 regulates DA and 5-HT uptake, accompanied with splicing efficiency and dependence-like behaviors in genomic association studies (2014)
  • Author(s): Uno K, Nishizawa D, Seo S, Sasaki N, Ohi K, Nabeshima T, Hashimoto R, Ozaki N, Ikeda K, Miyamoto Y, Nitta A
  • Organizer: 29th CINP World Congress of Neuropsychopharmacology
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2014-06-24
• [Presentation] Associations of an orexin (hypocretin) receptor 2 gene polymorphism with nicotine dependence found in genome-wide and following association studies (2014)
  • Author(s): Nishizawa D, Kasai S, Hasegawa J, Sato N, Tanioka F, Nagashima M, Ujike H, Hashimoto R, Tanaka M, Sugimura H, Ikeda K
  • Organizer: 29th CINP World Congress of Neuropsychopharmacology
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2014-06-23
• [Presentation] Personalized pain control (2014)
  • Author(s): Ikeda K, Nishizawa D, Hayashida M, Fukuda K
  • Organizer: 2014 YONSEI BK21 PLUS-IGAKUKEN Joint Symposium
  • Place of Presentation: Soul, Korea
  • Year and Date: 2014-06-20
  • Invited
• [Presentation] 遺伝子多型判定によるオピオイド性鎮痛薬必要量の予測式の構築と検証
  • Author(s): 吉田香織, 西澤大輔, 一宮尚志, 林田眞和, 福田謙一, 池田和隆
  • Organizer: 第23回日本臨床精神神経薬理学会・第43回日本神経精神薬理学会合同年会
  • Place of Presentation: 宜野湾
• [Presentation] Genome-wide association study identifies a potent locus associated with human opioid sensitivity
  • Author(s): Nishizawa D, Fukuda K, Kasai S, Hasegawa J, Nagashima M, Satoh Y, Higuchi S, Ujike H, Arinami T, Hayashida M, Ikeda K
  • Organizer: XXIst World Congress of Psychiatric Genetics
  • Place of Presentation: Boston, USA
• [Presentation] 様々な依存性物質の感受性に共通して関連する遺伝子多型
  • Author(s): 西澤大輔, 池田和隆
  • Organizer: 平成25年度アルコール・薬物依存関連学会合同学術総会
  • Place of Presentation: 岡山
  • Invited
• [Presentation] 依存性物質作用個人差の遺伝子メカニズムから探る依存のメカニズム
  • Author(s): 池田和隆, 西澤大輔
  • Organizer: Neuro2013
  • Place of Presentation: 京都
  • Invited
• [Presentation] Genome-wide association study identifies a potent locus associated with human opioid sensitivity
  • Author(s): Nishizawa D, Fukuda K, Kasai S, Hasegawa J, Aoki Y, Nishi A, Saita N, Koukita Y, Nagashima M, Katoh R, Satoh Y, Tagami M, Higuchi S, Ujike H, Ozaki N, Inada T, Iwata N, Sora I, Iyo M, Kondo N, Won MJ, Naruse N, Uehara K, Itokawa M, Koga M, Arinami T, Kaneko Y, Hayashida M, Ikeda K
  • Organizer: European Human Genetics Conference 2013
  • Place of Presentation: Paris, France
• [Presentation] テーラーメイド疼痛治療を開始して
  • Author(s): 福田謙一, 青木謙典, 西澤大輔, 高北義彦, 齋田菜緒子, 林田眞和, 一戸達也, 池田和隆
  • Organizer: 第33回日本臨床薬理学会学術総会
  • Place of Presentation: 宜野湾
• [Presentation] 様々な依存性物質の感受性に共通して関連する遺伝子多型
  • Author(s): 西澤大輔, 池田和隆
  • Organizer: 第22回日本臨床精神神経薬理学会・第42回日本神経精神薬理学会合同年会
  • Place of Presentation: 宇都宮
  • Invited
• [Remarks] 公益財団法人東京都医学総合研究所「依存性薬物プロジェクトホームページ」
  • URL: http://www.igakuken.or.jp/abuse/index.html
• [Remarks] 鎮痛にも依存にも影響するヒト遺伝子配列の差異を発見 ～網羅的ゲノム解析の成果～
  • URL: http://www.igakuken.or.jp/research/topics/2012/1128.html
• [Remarks] Discovery of "Pain Gene"...
  • URL: http://alert.psychiatricnews.org/2012/12/discovery-of-pain-gene-paves-way-to.html
• [Patent(Industrial Property Rights)] 各種鎮痛関連遺伝子解析による薬物感受性の評価方法 (2012)
  • Inventor(s): 池田和隆, 西澤大輔. 福田謙一
  • Industrial Property Rights Holder: 公益財団法人東京都医学総合研究所
  • Industrial Property Rights Type: 特許
  • Filing Date: 2012-12-21
  • Overseas
• [Patent(Industrial Property Rights)] サイクリックAMP応答配列結合タンパク質遺伝子解析による薬物感受性および疾患脆弱性の評価方法 (2012)
  • Inventor(s): 池田和隆, 西澤大輔. 福田謙一
  • Industrial Property Rights Holder: 公益財団法人東京都医学総合研究所
  • Industrial Property Rights Type: 特許
  • Filing Date: 2012-10-01
  • Overseas