Genome-wide association study to elucidate genetic pathogenesis of chronic postoperative pain

• Project/Area Number: 18K08829
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55050:Anesthesiology-related
• Research Institution: Juntendo University
• Principal Investigator: Hayashida Masakazu 順天堂大学, 医学部, 特任教授 (80251289)
• Co-Investigator(Kenkyū-buntansha): 池田 和隆 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, 分野長 (60281656) ; 西澤 大輔 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, 主席研究員 (80450584)
• Project Period (FY): 2018-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥390,000 (Direct Cost: ¥300,000、Indirect Cost: ¥90,000); Fiscal Year 2020: ¥260,000 (Direct Cost: ¥200,000、Indirect Cost: ¥60,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 婦人科良性疾患 / 腹腔鏡下手術 / オピオイド / 術後痛 / 遷延性術後痛 / 遺伝子多型 / ゲノムワイド関連解析 / 人科良性疾患 / 腹腔鏡下婦人科手術

Outline of Final Research Achievements

A genome-wide association study (GWAS) was performed in 333 patients who underwent gynecologic laparoscopic surgery to investigate genetic backgrounds underlying effects of opioid analgesics on acute intraoperative and postoperative pain and the development of chronic postoperative pain. The rs7858836 C/T SNP in the Astrotactin 2 gene potentiated the analgesic effect of fentanyl on postoperative pain, and the rs1799971 A/G SNP in the μ-opioid receptor gene attenuated the analgesic effect of remifentanil on intraoperative pain. Although the incidence of prolonged postoperative pain was low (12 cases, 3.6%), and the GWAS failed to identify SNPs that could be associated with the development of chronic pain, a multicenter study using an individual gene analysis showed that the rs11726196 G/T SNP in the Transient Receptor Potential Canonical Channel 3 gene could be associated with the development of chronic pain, including chronic postoperative pain.

Academic Significance and Societal Importance of the Research Achievements

今回の研究で、Astrotactin2遺伝子の一塩基多型(SNP)が術後フェンタニルの鎮痛効果を増強し、μ-opioid受容体遺伝子のSNPが術中レミフェンタニルの鎮痛効果を減弱させることが判明した。この結果は、我々の以前の研究も含む先行研究で得られた結果と一致し補強する所見と思われ、個別化鎮痛医療の発展に資すると考えられた。術後遷延痛も含む慢性痛の遺伝的背景に関する報告は未だに乏しいが、Transient Receptor Potential Canonicalチャネル3遺伝子のSNPの慢性術後痛への関与を見出した事は、慢性術後痛発生の病態生理解明に資する結果と思われた。

Research Products

• [Journal Article] rs11726196 single-nucleotide polymorphism of the transient receptor potential canonical 3 (TRPC3) gene is associated with chronic pain (2023)
  • Author(s): Aoki Y*, Nishizawa D*, Ohka S, Kasai S, Arita H, Hanaoka K, Yajima C, Iseki M, Kato J, Ogawa S, Hiranuma A, Hasegawa J, Nakayama K, Ebata Y, Ichinohe T, Hayashida M, Fukuda K, Ikeda K
  • Journal Title: Int J Mol Sci Volume: 24(2) Issue: 2 Pages: 1028-1028
  • DOI: 10.3390/ijms24021028
  • Peer Reviewed / Open Access
• [Journal Article] Postoperative analgesia following robot-assisted thoracic surgery for mediastinal disease: retrospective comparative study of general anesthesia alone, combined with epidural analgesia, and with ultrasound-guided thoracic paraspinal block (2023)
  • Author(s): Kusano Yukari、Kawagoe Izumi、Yamaguchi Ai、Kishii Jun、Morita Yuki、Fukuda Masataka、Kochiyama Tsukasa、Hayashida Masakazu
  • Journal Title: Annals of Translational Medicine Volume: 11 Issue: 5 Pages: 206-206
  • DOI: 10.21037/atm-22-4258
  • Peer Reviewed / Open Access
• [Journal Article] Genome-Wide Association Study Identifies Genetic Polymorphisms Associated with Estimated Minimum Effective Concentration of Fentanyl in Patients Undergoing Laparoscopic-Assisted Colectomy. (2023)
  • Author(s): Nishizawa D, Mieda T, Tsujita M, Nakagawa H, Yamaguchi S, Kasai, S, Hasegawa J, Nakayama K, Ebata Y, Kitamura A, Shimizu H, Takashima T, Hayashida M, Ikeda K.
  • Journal Title: Int J Mol Sci. Volume: 24 Issue: 9 Pages: 8421-8421
  • DOI: 10.3390/ijms24098421
  • Peer Reviewed / Open Access
• [Journal Article] Short Tandem Repeat Variation in the CNR1 Gene Associated With Analgesic Requirements of Opioids in Postoperative Pain Management (2022)
  • Author(s): Kasai S, Nishizawa D, Hasegawa J, Fukuda KI, Ichinohe T, Nagashima M, Hayashida M, Ikeda K.
  • Journal Title: Front Genet . Volume: 13 Pages: 815089-815089
  • DOI: 10.3389/fgene.2022.815089
  • Peer Reviewed / Open Access
• [Journal Article] Associations between the C3orf20 rs12496846 Polymorphism and Both Postoperative Analgesia after Orthognathic and Abdominal Surgeries and C3orf20 Gene Expression in the Brain (2022)
  • Author(s): Nishizawa D, Nagashima M, Kasai S, Hasegawa J, Nakayama K, Ebata Y, Fukuda KI, Ichinohe T, Hayashida M, Ikeda K.
  • Journal Title: Pharmaceutics Volume: 14 Issue: 4 Pages: 727-727
  • DOI: 10.3390/pharmaceutics14040727
  • Peer Reviewed / Open Access
• [Journal Article] A Comparison Between Effects of Amenamevir and Famciclovir on Intensities of Acute Pain and the Incidence of Postherpetic Neuralgia in Adult Patients with Herpes Zoster (2022)
  • Author(s): Kageshima Y, Inada E, Yamaguchi K, Hayashida M.
  • Journal Title: Juntendo Medical Journal Volume: 68 Issue: 2 Pages: 120-130
  • DOI: 10.14789/jmj.JMJ21-0036-OA
  • ISSN: 2187-9737, 2188-2126
  • Peer Reviewed / Open Access
• [Journal Article] Novel opioid analgesics for the development of transdermal opioid patches that possess morphine-like pharmacological profiles rather than fentanyl: possible opioid switching alternatives among patch formula. (2022)
  • Author(s): 2.Komatsu A, Miyano K, Nakayama D, Mizobuchi Y, Uezono E, Ohshima K, Karasawa Y, Kuroda Y, Nonaka M, Yamaguchi K, Iseki M, Uezono Y, Hayashida M.
  • Journal Title: Anesth Analg Volume: 134 Issue: 5 Pages: 1082-1093
  • DOI: 10.1213/ane.0000000000005954
  • Peer Reviewed / Open Access
• [Journal Article] Anti-inflammatory action of dexmedetomidine on human microglial cells. (2022)
  • Author(s): Yamazaki S, Yamaguchi K, Someya A, Nagaoka I, Hayashida M
  • Journal Title: Int J Mol Sci Volume: 23 Issue: 17 Pages: 10096-10096
  • DOI: 10.3390/ijms231710096
  • Peer Reviewed / Open Access
• [Journal Article] valuation of the intracellular signaling activities of κ opioid receptor agonists, nalfurafine analogs; focusing on the selectivity of G protein- and β-arrestin-mediated pathways. (2022)
  • Author(s): Yamaguchi, M., Miyano, K., Hirayama, S., Karasawa, Y., Oshima, K., Uezono, E., Komatsu, A., Nonaka, M., Fujii, H., Yamaguchi, K., Iseki, M., Hayashida, M., Uezono, Y.
  • Journal Title: Molecules Volume: 27 Issue: 20 Pages: 7065-7065
  • DOI: 10.3390/molecules27207065
  • Peer Reviewed / Open Access
• [Journal Article] Historical Changes in Anesthesia Practice for Laparoscopic Gynecological Surgery at Juntendo University Hospital – A Retrospective Observational Study Focusing on Factors Affecting the Incidence of Postoperative Nausea and Vomiting (2022)
  • Author(s): Kudoh O, Hayashida M.
  • Journal Title: Juntendo Medical Journal Volume: 68 Issue: 6 Pages: 582-589
  • DOI: 10.14789/jmj.JMJ22-0013-OA
  • ISSN: 2187-9737, 2188-2126
  • Peer Reviewed / Open Access
• [Journal Article] Genome-wide association study identifies candidate loci associated with chronic pain and postherpetic neuralgia (2021)
  • Author(s): Nishizawa D, Iseki M, Arita H, Hanaoka K, Yajima C, Kato J, Ogawa S, Hiranuma A, Kasai S, Hasegawa J, Hayashida M, Ikeda K
  • Journal Title: Mol Pain Volume: 17 Pages: 174480692199992-174480692199992
  • DOI: 10.1177/1744806921999924
  • Peer Reviewed / Open Access
• [Journal Article] Effects of rs958804 and rs7858836 single-nucleotide polymorphisms of the ASTN2 gene on pain-related phenotypes in patients who underwent laparoscopic colectomy and mandibular sagittal split ramus osteotomy (2021)
  • Author(s): Inoue R, Nishizawa D, Hasegawa J, Nakayama K, Fukuda K, Ichinohe T, Mieda T, Tsujita M, Nakagawa H, Kitamura A, Sumikura H, Ikeda K, Hayashida M
  • Journal Title: Neuropsychopharmacol Rep Volume: 41(1) Issue: 1 Pages: 82-90
  • DOI: 10.1002/npr2.12159
  • Peer Reviewed / Open Access
• [Journal Article] Heparan sulfate 3-O-sulfotransferase 4 is genetically associated with herpes zoster and enhances varicella-zoster virus-mediated fusogenic activity. (2021)
  • Author(s): Ohka S, Yamada S, Nishizawa D, Fukui Y, Arita H, Hanaoka K, Iseki M, Kato J, Ogawa S, Hiranuma A, Kasai S, Hasegawa J, Hayashida M, Fukushi S, Saijo M, Ikeda AK.
  • Journal Title: Mol Pain. Volume: 17 Pages: 174480692110521-174480692110521
  • DOI: 10.1177/17448069211052171
  • Peer Reviewed / Open Access
• [Journal Article] Free triiodothyronine (fT3) and B-type natriuretic peptide (BNP) predict in-hospital mortality after valve surgery. (2020)
  • Author(s): Mukaida H, Hayashida M, Matsushita S, Endo D, Oishi A, Shimada A, Hata H, Kajimoto K, Yamamoto T, Amano A.
  • Journal Title: Gen Thorac Cardiovasc Surg. Volume: 68 Issue: 6 Pages: 585-595
  • DOI: 10.1007/s11748-019-01244-x
  • Peer Reviewed / Open Access
• [Journal Article] Intercostal misplacement of a thoracic epidural catheter discovered during lung cancer surgery: a case report. (2019)
  • Author(s): Kawagoe I, Hayashida M, Satoh D, Inada E.
  • Journal Title: JA Clin Rep. Volume: 5 Issue: 1 Pages: 44-44
  • DOI: 10.1186/s40981-019-0264-8
  • Peer Reviewed / Open Access
• [Journal Article] Association between the rs7583431 single-nucleotide polymorphism close to the activating transcription factor 2 (ATF2) gene and the analgesic effect of fentanyl in the cold pain test. (2018)
  • Author(s): Aoki Y, Nishizawa D, Yoshida K, Hasegawa J, Kasai S, Takahashi K, Koukita Y, Ichinohe T, Hayashida M, Fukuda K, Ikeda K
  • Journal Title: Neuropsychopharmacology Rep Volume: 印刷中 Issue: 2 Pages: 86-91
  • DOI: 10.1002/npr2.12012
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genome-wide scan identifies candidate loci related to remifentanil requirements during laparoscopic-assisted colectomy. (2018)
  • Author(s): 2.Nishizawa D, Mieda T, Tsujita M, Nakagawa H, Yamaguchi S, Kasai S, Hasegawa J, Fukuda KI, Kitamura A, Hayashida M, Ikeda K.
  • Journal Title: Pharmacogenomics Volume: 19 Issue: 2 Pages: 113-127
  • DOI: 10.2217/pgs-2017-0109
  • Peer Reviewed
• [Presentation] ASTN2遺伝子上の2つの一塩基多型rs958804とrs7858836が婦人科良性疾患に対する腹腔鏡手術を受けた患者における疼痛関連表現型に及ぼす影響． (2023)
  • Author(s): 井上理恵，林田眞和，西澤大輔，角倉弘行，池田和隆．
  • Organizer: 日本麻酔科学会第70回学術集会
• [Presentation] Genetic mechanisms underlying individual differences in opioid sensitivity revealed by genome-wide association studies. (2022)
  • Author(s): Ikeda K, Nishizawa D, Hayashida M, Fukuda K..
  • Organizer: 33rd CINP World Congress of Neuropharmacology
  • Int'l Joint Research / Invited
• [Presentation] Association of a single nucleotide polymorphism rs12496846 in the C3orf20 gene region, identified to be associated with postoperative analgesia after mandibular sagittal split ramus osteotomy, with postoperative analgesia after major abdominal surgery and C3orf20 gene expression in the brain. (2022)
  • Author(s): Nishizawa D, Nagashima S, Kasai S, Hasegawa J, Nakayama K, Ebata Y, Hayashida M, Ikeda K.
  • Organizer: 33rd CINP World Congress of Neuropsychopharmacology
  • Int'l Joint Research
• [Presentation] rs2243057 single nucleotide polymorphism of the protease-activated receptor 2 gene associated with pain sensitivity and chronic pain. (2021)
  • Author(s): Soeda M, Ohka S, Nishizawa D, Manabu S, Hasegawa J, Iseki M, Hiranuma A, Arita H, Hanaoka K, Yajima C, Kato J, Ogawa S, Kasai S, Ebata Y, Nakayama K, Hayashida M, Fukuda K, Ichinohe T, Ikeda K
  • Organizer: CINP 2021 Virtual World Congress
  • Int'l Joint Research
• [Presentation] A gene related to herpes zoster or post-herpetic neuralgia has impacts on varicella-zoster virus infection or replication. (2021)
  • Author(s): Ohka S, Nishizawa D, Yamada S, Hasegawa J, Fukui Y, Iseki M, Hiranuma A, Arita H, Hanaoka K, Yajima C, Kato J, Ogawa S, Kasai S, Ebata Y, Nakayama K, Hayashida M, Fukushi S, Saijo M, Ikeda K.
  • Organizer: CINP 2021 Virtual World Congress
  • Int'l Joint Research
• [Presentation] Genome-wide association study identifies genetic polymorphisms associated with estimated minimal effective analgesic concentration of fentanyl in patients undergoing laparoscopic-assisted colectomy. (2021)
  • Author(s): Nishizawa D, Mieda T, Tsujita M, Nakagawa H, Yamaguchi S, Kasai S, Hasegawa J, Nakayama K, Ebata Y, Kitamura A, Shimizu H, Takashima T, Hayashida M, Ikeda K
  • Organizer: CINP 2021 Virtual World Congress
  • Int'l Joint Research
• [Presentation] A gene associated with herpes zoster or post-herpetic neuralgia affects varicella-zoster virus infection or replication. (2020)
  • Author(s): Ohka S, Nishizawa D, Yamada S, Hasegawa J, Fukui Y, Iseki M, Arita H, Hanaoka K, Kato J, Ogawa S, Hiranuma A, Kasai S, Nakayama K, Ebata Y, Hayashida M, Fukushi S, Saijo M, Ikeda K
  • Organizer: 59th Annual Meeting of The American College of Neuropsychopharmacology (ACNP 2020)
  • Int'l Joint Research
• [Presentation] 臨床につながる遺伝子研究アップデート. (2019)
  • Author(s): 池田和隆, 西澤大輔, 井関雅子, 林田眞和, 福田謙一
  • Organizer: 第39回鎮痛薬・オピオイドペプチドシンポジウム, 東京 [2019/08/24]
  • Invited
• [Presentation] Personalized opioid use for controlling pain and drug abuse. (2019)
  • Author(s): Ikeda K, Nishizawa D, Hayashida M, Fukuda K
  • Organizer: The 10th IBRO World Congress of Neuroscience (IBRO2019), Daegu, Korea [2019/09/22].
  • Int'l Joint Research / Invited
• [Presentation] Associations between genetic polymorphisms on chromosome 14q32 and effects of opioid analgesics and chronic pain. (2019)
  • Author(s): Kosaki Y, Nishizawa D, Arita H, Hanaoka K, Yajima C, Iseki M, Kato J, Ogawa S, Hiranuma A, Kasai S, Hasegawa J, Nakayama K, Ebata Y, Koukita Y, Ichinohe T, Hayashida M, Fukuda K, Ikeda K
  • Organizer: 6th Congress of Asian College of Neuropsychopharmacology (AsCNP2019), Fukuoka [2019/10/12].
  • Int'l Joint Research
• [Presentation] Association of a candidate locus for human opioid sensitivity identified in a genome-wide association study in patients undergoing laparoscopic-assisted colectomy with postoperative opioid requirements in patients undergoing painful cosmetic surgery. (2019)
  • Author(s): Inoue R, Nishizawa D, Hasegawa J, Nakayama K, Fukuda K, Sumikura H, Hayashida M, Ikeda K
  • Organizer: 6th Congress of Asian College of Neuropsychopharmacology (AsCNP2019), Fukuoka [2019/10/12].
  • Int'l Joint Research
• [Presentation] Genome-wide association studies on chronic pain and effects of drugs for the treatment of pain. (2019)
  • Author(s): Nishizawa D, Arita H, Hanaoka K, Yajima C, Iseki M, Kato J, Ogawa S, Hiranuma A, Kasai S, Hasegawa J, Ebata Y, Nakayama K, Hayashida M, Ikeda K
  • Organizer: 6th Congress of Asian College of Neuropsychopharmacology (AsCNP2019), Fukuoka [2019/10/13].
  • Int'l Joint Research
• [Presentation] Association between the rs11726196 Single-Nucleotide Polymorphism within the Transient Receptor Subfamily C Member 3 (TRPC3) Gene and Chronic Pain. (2019)
  • Author(s): Aoki Y, Nishizawa D, Yoshida K, Arita H, Hanaoka K, Yajima C, Iseki M, Kato J, Ogawa S, Hiranuma A, Hasegawa J, Kasai S, Takahashi K, Koukita Y, Ichinohe T, Hayashida M, Fukuda K, Ikeda K
  • Organizer: 6th Congress of Asian College of Neuropsychopharmacology (AsCNP2019), Fukuoka [2019/10/13].
  • Int'l Joint Research
• [Presentation] Genome-wide association study identifies genetic polymorphisms and genes possibly associated with chronic pain and postherpetic neuralgia. (2019)
  • Author(s): Nishizawa D, Arita H, Hanaoka K, Yajima C, Iseki M, Kato J, Ogawa S, Hiranuma A, Kasai S, Hasegawa J, Ebata Y, Nakayama K, Hayashida M, Ikeda K
  • Organizer: The 69th Annual Meeting of the American Society of Human Genetics (ASHG2019), Houston, USA [2019/10/17]
  • Int'l Joint Research
• [Presentation] ゲノムワイド関連解析(GWAS)による慢性痛及び帯状疱疹後神経痛感受性遺伝子の同定. (2019)
  • Author(s): 西澤大輔, 有田英子, 花岡一雄, 矢島直, 井関雅子, 加藤実, 小川節郎, 平沼彩子, 笠井慎也, 長谷川準子, 江畑裕子, 中山京子, 林田眞和, 池田和隆
  • Organizer: 日本人類遺伝学会第64回大会, 長崎 [2019/11/07].
• [Book] オピオイド受容体遺伝子を含む関連遺伝子とオピオイド感受性－がん性疼痛オピオイド治療の将来へ向けて. In: がん性疼痛 薬の使い方 (花岡一雄編) (2022)
  • Author(s): 林田眞和, 西澤大輔, 池田和隆.
  • Total Pages: 8
  • Publisher: 克誠堂出版
  • ISBN: 9784771905610
• [Book] 筋弛緩薬. 今日の治療薬（2022年版）．島田和幸，川合眞一，伊豆津宏二，今井靖（編集) (2022)
  • Author(s): 林田眞和．
  • Total Pages: 8
  • Publisher: 南江堂
  • ISBN: 9784524232116
• [Book] 麻薬および類似薬. 今日の治療薬（2022年版）．島田和幸，川合眞一，伊豆津宏二，今井靖（編集) (2022)
  • Author(s): 林田眞和．
  • Total Pages: 17
  • Publisher: 南江堂
  • ISBN: 9784524232116
• [Book] 麻酔薬. 今日の治療薬（2022年版）．島田和幸，川合眞一，伊豆津宏二，今井靖（編集) (2022)
  • Author(s): 林田眞和．
  • Total Pages: 14
  • Publisher: 南江堂
  • ISBN: 9784524232116