A Series of Genes for Predicting Responses to Anti-Tumor Necrosis Factor α Therapy in Crohn’s Disease
Background: Patients with Crohn’s disease (CD) experience severely reduced quality of life, particularly those who do not respond to conventional therapies. Antitumor necrosis factor (TNF)α is commonly used as first-line therapy; however, many patients remain unresponsive to this treatment, and the...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-04-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.870796/full |
| _version_ | 1818058637602455552 |
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| author | Kai Nie Chao Zhang Minzi Deng Weiwei Luo Kejia Ma Jiahao Xu Xing Wu Yuanyuan Yang Xiaoyan Wang Xiaoyan Wang |
| author_facet | Kai Nie Chao Zhang Minzi Deng Weiwei Luo Kejia Ma Jiahao Xu Xing Wu Yuanyuan Yang Xiaoyan Wang Xiaoyan Wang |
| author_sort | Kai Nie |
| collection | DOAJ |
| description | Background: Patients with Crohn’s disease (CD) experience severely reduced quality of life, particularly those who do not respond to conventional therapies. Antitumor necrosis factor (TNF)α is commonly used as first-line therapy; however, many patients remain unresponsive to this treatment, and the identification of response predictors could facilitate the improvement of therapeutic strategies.Methods: We screened Gene Expression Omnibus (GEO) microarray cohorts with different anti-TNFα responses in patients with CD (discovery cohort) and explored the hub genes. The finding was confirmed in independent validation cohorts, and multiple algorithms and in vitro cellular models were performed to further validate the core predictor.Results: We screened four discovery datasets. Differentially expressed genes between anti-TNFα responders and nonresponders were confirmed in each cohort. Gene ontology enrichment revealed that innate immunity was involved in the anti-TNFα response in patients with CD. Prediction analysis of microarrays provided the minimum misclassification of genes, and the constructed network containing the hub genes supported the core status of TLR2. Furthermore, GSEA also supports TLR2 as the core predictor. The top hub genes were then validated in the validation cohort (GSE159034; p < 0.05). Furthermore, ROC analyses demonstrated the significant predictive value of TLR2 (AUC: 0.829), TREM1 (AUC: 0.844), and CXCR1 (AUC: 0.841). Moreover, TLR2 expression in monocytes affected the immune–epithelial inflammatory response and epithelial barrier during lipopolysaccharide-induced inflammation (p < 0.05).Conclusion: Bioinformatics and experimental research identified TLR2, TREM1, CXCR1, FPR1, and FPR2 as promising candidates for predicting the anti-TNFα response in patients with Crohn’s disease and especially TLR2 as a core predictor. |
| first_indexed | 2024-12-10T13:03:48Z |
| format | Article |
| id | doaj.art-a7e706f2c6304026a3170a7f6801fd59 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-10T13:03:48Z |
| publishDate | 2022-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-a7e706f2c6304026a3170a7f6801fd592022-12-22T01:47:55ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-04-011310.3389/fphar.2022.870796870796A Series of Genes for Predicting Responses to Anti-Tumor Necrosis Factor α Therapy in Crohn’s DiseaseKai Nie0Chao Zhang1Minzi Deng2Weiwei Luo3Kejia Ma4Jiahao Xu5Xing Wu6Yuanyuan Yang7Xiaoyan Wang8Xiaoyan Wang9Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, ChinaDepartment of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, ChinaDepartment of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, ChinaDepartment of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, ChinaDepartment of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, ChinaDepartment of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, ChinaDepartment of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, ChinaDepartment of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, ChinaDepartment of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, ChinaHunan Key Laboratory of Nonresolving Inflammation and Cancer, Cancer Research Institute, Central South University, Changsha, ChinaBackground: Patients with Crohn’s disease (CD) experience severely reduced quality of life, particularly those who do not respond to conventional therapies. Antitumor necrosis factor (TNF)α is commonly used as first-line therapy; however, many patients remain unresponsive to this treatment, and the identification of response predictors could facilitate the improvement of therapeutic strategies.Methods: We screened Gene Expression Omnibus (GEO) microarray cohorts with different anti-TNFα responses in patients with CD (discovery cohort) and explored the hub genes. The finding was confirmed in independent validation cohorts, and multiple algorithms and in vitro cellular models were performed to further validate the core predictor.Results: We screened four discovery datasets. Differentially expressed genes between anti-TNFα responders and nonresponders were confirmed in each cohort. Gene ontology enrichment revealed that innate immunity was involved in the anti-TNFα response in patients with CD. Prediction analysis of microarrays provided the minimum misclassification of genes, and the constructed network containing the hub genes supported the core status of TLR2. Furthermore, GSEA also supports TLR2 as the core predictor. The top hub genes were then validated in the validation cohort (GSE159034; p < 0.05). Furthermore, ROC analyses demonstrated the significant predictive value of TLR2 (AUC: 0.829), TREM1 (AUC: 0.844), and CXCR1 (AUC: 0.841). Moreover, TLR2 expression in monocytes affected the immune–epithelial inflammatory response and epithelial barrier during lipopolysaccharide-induced inflammation (p < 0.05).Conclusion: Bioinformatics and experimental research identified TLR2, TREM1, CXCR1, FPR1, and FPR2 as promising candidates for predicting the anti-TNFα response in patients with Crohn’s disease and especially TLR2 as a core predictor.https://www.frontiersin.org/articles/10.3389/fphar.2022.870796/fullCrohn’s diseaseantitumor necrosis factor α therapydrug responsedifferentially expressed geneshub genes |
| spellingShingle | Kai Nie Chao Zhang Minzi Deng Weiwei Luo Kejia Ma Jiahao Xu Xing Wu Yuanyuan Yang Xiaoyan Wang Xiaoyan Wang A Series of Genes for Predicting Responses to Anti-Tumor Necrosis Factor α Therapy in Crohn’s Disease Frontiers in Pharmacology Crohn’s disease antitumor necrosis factor α therapy drug response differentially expressed genes hub genes |
| title | A Series of Genes for Predicting Responses to Anti-Tumor Necrosis Factor α Therapy in Crohn’s Disease |
| title_full | A Series of Genes for Predicting Responses to Anti-Tumor Necrosis Factor α Therapy in Crohn’s Disease |
| title_fullStr | A Series of Genes for Predicting Responses to Anti-Tumor Necrosis Factor α Therapy in Crohn’s Disease |
| title_full_unstemmed | A Series of Genes for Predicting Responses to Anti-Tumor Necrosis Factor α Therapy in Crohn’s Disease |
| title_short | A Series of Genes for Predicting Responses to Anti-Tumor Necrosis Factor α Therapy in Crohn’s Disease |
| title_sort | series of genes for predicting responses to anti tumor necrosis factor α therapy in crohn s disease |
| topic | Crohn’s disease antitumor necrosis factor α therapy drug response differentially expressed genes hub genes |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.870796/full |
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