Development of a diagnostic method for severe cutaneous adverse reactions by genom biomarkers and their pathophysiological relevanceic

• Project/Area Number: 26293122
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Applied pharmacology
• Research Institution: National Institute of Health Sciences
• Principal Investigator: Saito Yoshiro 国立医薬品食品衛生研究所, 医薬安全科学部, 部長 (50215571)
• Co-Investigator(Kenkyū-buntansha): 関根 章博 千葉大学, 予防医学センター, 教授 (30425631) ; 中村 亮介 国立医薬品食品衛生研究所, 医薬安全科学部, 室長 (50333357) ; 高橋 幸利 独立行政法人国立病院機構(静岡・てんかん神経医療センター臨床研究部), その他部局等, その他 (70262764) ; 相原 道子 横浜市立大学, 医学研究科, 教授 (90231753)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥16,510,000 (Direct Cost: ¥12,700,000、Indirect Cost: ¥3,810,000); Fiscal Year 2016: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2015: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2014: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
• Keywords: ゲノム / バイオマーカー / 薬剤反応性 / トランスレーショナルリサーチ / 副作用

Outline of Final Research Achievements

Lamotrigine, a drug for epileptics and bipolar disorder, is known to frequently cause severe cutaneous adverse reactions such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN). We conducted HLA and genome-wide genetic polymorphism analysis of Japanese patients with SJS/TEN, and using the healthy adults' data as controls, we found plural significantly associated genetic polymorphisms even after correction of multiple comparison. The results should be validated using another set of patient/control samples. On the other hand, no significant HLA type has been found after the correction.

Research Products

• [Journal Article] Pharmacogenomic information in the Warning section of drug labels: A comparison between labels in the United States and those in five other countries/regions. (2018)
  • Author(s): Imatoh T, Sai K, Saito Y
  • Journal Title: J Clin Pharm Ther. Volume: 43 Issue: 4 Pages: 493-499
  • DOI: 10.1111/jcpt.12691
  • Peer Reviewed
• [Journal Article] Plasma Lipid Profiling of Patients with Chronic Ocular Complications Caused by Stevens Johnson Syndrome/Toxic Epidermal Necrolysis (2016)
  • Author(s): Saito K, Ueta M, Maekawa K, Sotozono C, Kinoshita S, Saito Y
  • Journal Title: PLoS One Volume: 11 Issue: 11 Pages: e0167402-e0167402
  • DOI: 10.1371/journal.pone.0167402
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinical pharmacogenetics implementation consortium (CPIC) guidelines for human leukocyte antigen B (HLA-B) genotype and allopurinol dosing: 2015 update. (2016)
  • Author(s): Saito Y, Stamp LK, Caudle KE, Hershfield M, McDonagh EM, Callagham JT, Tassaneeyakul W, Mushiroda T, Kamatani N, Goldspiel BR, Phillips EJ, Klein TE, Lee MTM
  • Journal Title: Clin. Pharmacol. Ther. Volume: 99 Issue: 1 Pages: 36-37
  • DOI: 10.1002/cpt.161
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Predictive Genomic Markers for Severe Adverse Drug Reactions (2015)
  • Author(s): Saito Y, Kodama S, Sugiyama E, Nakamura R.
  • Journal Title: YAKUGAKU ZASSHI Volume: 135 Issue: 4 Pages: 589-595
  • DOI: 10.1248/yakushi.14-00249-3
  • NAID: 130005060821
  • ISSN: 0031-6903, 1347-5231
  • Year and Date: 2015-04-01
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Japan Pharmacogenomics Data Science Consortium. Development of a simple genotyping method for the HLA-A*31:01-tagging SNP in Japanese. (2015)
  • Author(s): Maekawa K, Nakamura R, Kaniwa N, Mizusawa S, Kitamoto A, Kitamoto T, Ukaji M, Matsuzawa Y, Sugiyama E, Uchida Y, Kurose K, Ueta M, Sotozono C, Ikeda H, Yagami A, Matsukura S, Kinoshita S, Muramatsu M, Ikezawa Z, Sekine A, Furuya H, Takahashi Y, Matsunaga K, Aihara M, Saito Y
  • Journal Title: Pharmacogenomics. Volume: 16 Issue: 15 Pages: 1689-1699
  • DOI: 10.2217/pgs.15.115
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Drugs causing severe ocular surface involvements in Japanese patients with StevenseJohnson syndrome/toxic epidermal necrolysis (2015)
  • Author(s): Kaniwa N, Ueta M, Nakamura R, Okamoto-Uchida Y, Sugiyama E, Maekawa K, Takahashi Y, Furuya H, Yagami A, Matsukura S, Ikezawa Z, Matsunaga K, Sotozono C, Aihara M, Kinoshita S, Saito Y.
  • Journal Title: Allergology International Volume: 64 Issue: 4 Pages: 379-381
  • DOI: 10.1016/j.alit.2015.05.002
  • NAID: 130005290406
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Independent strong association of HLA-A*02:06 and HLA-B*44:03 with cold medicine-related Stevens-Johnson syndrome with severe mucosal involvement. (2014)
  • Author(s): Ueta M, Kaniwa N, Sotozono C, Tokunaga K, Saito Y, Sawai H, Miyadera H, Sugiyama E, Maekawa K, Nakamura R, Nagato M, Aihara M, Matsunaga K, Takahashi Y, Furuya H, Muramatsu M, Ikezawa Z, Kinoshita S.
  • Journal Title: Sci Rep. Volume: 4 Issue: 1 Pages: 4862-4862
  • DOI: 10.1038/srep04862
  • Peer Reviewed / Open Access
• [Presentation] Introduction to the skin as a target for immune-mediated drug hypersensitivity (2017)
  • Author(s): Yoshiro Saito
  • Organizer: Society of Toxicology, 56th Annual Meeting and ToxExpo
  • Place of Presentation: USA, Baltimore
  • Year and Date: 2017-03-15
  • Int'l Joint Research / Invited
• [Presentation] Genomic biomarkers and patients’ background information for onset of SJS/TEN (2017)
  • Author(s): Yoshiro Saito, Ryosuke Nakamura
  • Organizer: 2nd International Stevens-Johnson Syndrome Symposium
  • Place of Presentation: Kyoto
  • Year and Date: 2017-01-22
  • Int'l Joint Research / Invited
• [Presentation] オミックス解析による副作用バイオマーカー開発の進展 (2017)
  • Author(s): 斎藤嘉朗
  • Organizer: 第38回日本臨床薬理学会学術集会
  • Invited
• [Presentation] 副作用回避へのバイオマーカー情報の応用と課題 (2017)
  • Author(s): 斎藤嘉朗
  • Organizer: 第55回日本癌治療学会学術集会
  • Invited
• [Presentation] 医薬品適正使用のためのバイオマーカーおよび薬剤疫学的情報の活用 (2016)
  • Author(s): 斎藤嘉朗
  • Organizer: 第66回日本薬学会近畿支部大会
  • Place of Presentation: 大阪
  • Year and Date: 2016-10-15
  • Invited
• [Presentation] バイオマーカー開発の現状と課題 (2016)
  • Author(s): 斎藤嘉朗
  • Organizer: 第6回レギュラトリーサイエンス学会学術大会
  • Place of Presentation: 東京
  • Year and Date: 2016-09-10
  • Invited
• [Presentation] Biomarker regulation and regulatory sciences in Japan (2016)
  • Author(s): Yoshiro Saito
  • Organizer: 11th International ISSX meeting
  • Place of Presentation: 韓国 釜山
  • Year and Date: 2016-06-14
  • Int'l Joint Research / Invited
• [Presentation] Genomic markers associated with Stevens-Johnson syndrome/epidermal necrolysis in Japan; A JSAR group study. (2016)
  • Author(s): Saito Y and Nakamura R
  • Organizer: 1st International Stevens-Johnson Syndrome Symposium
  • Place of Presentation: 京都
  • Year and Date: 2016-01-24
  • Int'l Joint Research / Invited
• [Presentation] 国内の動向：臨床試料を用いた安全性バイオマーカー探索と検証 ―セーフティートランスレーションにおける課題―. (2015)
  • Author(s): 斎藤嘉朗, 前川京子, 齊藤公亮, 中村亮介, 熊谷雄治
  • Organizer: 第42回 日本毒性学会学術年会
  • Place of Presentation: 金沢
  • Year and Date: 2015-06-30
  • Invited
• [Presentation] 重症眼粘膜障害を伴うSJS/TENの発症と関連する被疑薬およびHLA型について. (2015)
  • Author(s): 中村亮介, 鹿庭なほ子, 上田真由美, 岡本(内田)好海, 杉山永見子, 高橋幸利, 古谷博和, 矢上晶子, 松倉節子, 池澤善郎, 松永佳世子, 徳永勝士, 外園千恵, 相原道子, 木下茂, 斎藤嘉朗
  • Organizer: 第64回日本アレルギー学会学術大会
  • Place of Presentation: 東京
  • Year and Date: 2015-05-26
• [Presentation] 日本人におけるカルバマゼピン誘因性薬疹発症の危険因子HLA-A*31:01 のサロゲートマーカー多型を対象としたタイピング系の構築． (2015)
  • Author(s): 前川京子, 水澤精穂, 北本綾, 北本卓也, 中村亮介, 杉山永見子, 上田真由美, 外園千恵, 池田浩子, 矢上晶子, 松倉節子, 木下茂, 村松正明, 古谷博和, 高橋幸利, 松永佳世子, 相原道子, 関根章博, 日本PGX データサイエンスコンソーシアム, 斎藤嘉朗
  • Organizer: 日本薬学会第135年会
  • Place of Presentation: 神戸市
  • Year and Date: 2015-03-26 – 2015-03-28
• [Presentation] ヒト試料を用いたバイオマーカー開発のためのレギュラトリーサイエンス. (2014)
  • Author(s): 斎藤嘉朗，齊藤公亮，児玉進，熊谷雄治，前川京子
  • Organizer: 第35回日本臨床薬理学会学術総会
  • Place of Presentation: 愛媛県松山市
  • Year and Date: 2014-12-04 – 2014-12-06
  • Invited
• [Presentation] HLA association with antipyretic analgesics-induced Stevens-Johnson syndrome / toxic epidermal necrolysis with severe ocular surface complications in Japanese patients. (2014)
  • Author(s): Nakamura R, Kaniwa N, Ueta M, Sotozono C, Sugiyama E, Maekawa K, Yagami A, Matsukura S, Ikezawa Z, Matsunaga K, Tokunaga K, Aihara M, Kinoshita S, Saito Y
  • Organizer: EAACI Drug Hypersensitivity Meeting, DHM 2014
  • Place of Presentation: Bern, Switzerland
  • Year and Date: 2014-04-09 – 2014-04-12
• [Presentation] Medication tendencies for inducing severe ocular surface symptoms in Japanese Stevens-Johnson syndrome / toxic epidermal necrolysis patients. (2014)
  • Author(s): Saito Y, Ueta M, Nakamura R, Sugiyama E, Maekawa K, Takahashi Y, Furuya H, Yagami A, Matsukura S, Ikezawa Z, Matsunaga K, Sotozono C, Aihara M, Kinoshita S, Kaniwa N
  • Organizer: EAACI Drug Hypersensitivity Meeting, DHM 2014
  • Place of Presentation: Bern, Switzerland
  • Year and Date: 2014-04-09 – 2014-04-12