Establishment of DNA-based diagnosis and elucidation of molecular mechanisms for response and loss of response to infliximab at short or long period of treatment against Crohn's disease
| Project/Area Number |
16K08912
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Applied pharmacology
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| Research Institution | Nagasaki University |
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Principal Investigator |
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| Project Period (FY) |
2016-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | クローン病 / インフリキシマブ / 薬剤応答性遺伝子 / 治療感受性の機序解明 / 治療抵抗性の機序解明 / 遺伝子診断 / ゲノム創薬 / 治療効果消失の機序解明 / 治療感受性遺伝子 / 治療抵抗性遺伝子 / 腫瘍壊死因子シグナル共有経路 / P2RX7シグナル経路 / レミケード / 効果予測の遺伝子診断法 |
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| Outline of Final Research Achievements |
Infliximab (IFX) is a monoclonal antibody exerting the therapeutic effect for Crohn’s disease (CD). We examined an association study of 162 tag single nucleotide polymorphisms in 32 candidate genes with response to IFX at the 10-weeks or 1-year period of treatment for Japanese 127 CD patients, identifying 6 and 9 IFX-responsibility genes at the 10-weeks and 1-year period, respectively.
Multivariate analyses and genetic tests revealed that the best combination of polymorphisms of TRAF2 and TLR2 is useful as a biomarker for identifying responders to IFX at the 10-weeks period of treatment. Likewise, a combination of polymorphisms of CD40, P2RX7, and CASP1 is most suitable for identifying responders at the 1-year period of treatment against CD patients.
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| Academic Significance and Societal Importance of the Research Achievements |
クローン病患者に対するインフリキシマブ治療において，投与開始10週後も治療効果が持続する患者と治療効果が消失する患者では，どのような遺伝的背景であるかを解明できた。同様に，投与開始1年後の治療効果についても解明できた。さらに，10週後と1年後に関与する遺伝子は異なり，病態の分子機序が異なっていた。
治療効果に関与していた遺伝子をバイオマーカーに用いた遺伝子診断法を開発した。インフリキシマブを投与する前にクローン病患者の10週後と1年後の治療効果あるいは治療効果消失が予測でき，個々の患者に最適の治療戦略を立案できる材料を提供できたことは，今後の個別化治療につながる成果であった。
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Report
(5 results)
Research Products
(15 results)
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[Journal Article] The evidence of genetic polymorphisms of genes involved in the P2RX7 signaling pathway as predictive biomarkers for response and loss of response to infliximab against Crohn's disease2016
Author(s)
Araki C, Yoshimura M, Fukumitsu Y, Ma S, Ishida T, Urabe S, Matsushima K, Honda T, Uehara R, Fukuda Y, Takeshima F, Higuchi N, Isomoto H, Nakao K, Tsukamoto K
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Journal Title
Integrative Molecular Medicine
Volume: 3
Issue: 6
Pages: 1-15
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Presentation] Associations between a polymorphism of the gene encoding the Toll like receptor and response to infliximab in Japanese patients with Crohn’s disease2017
Author(s)
Ma S, Fukumitsu Y, Noma Y, Inamine T, Kondo S, Urabe S, Matsushima K, Uehara R, Honda T, Machida H, Yamaguchi N, Ohnita K, Takeshima F, Isomoto H, Nakao K, Tsukamoto K
Organizer
67th American Society of Human Genetics Annual Meeting
Related Report
Int'l Joint Research
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