Construction of a molecular inflammatory predictive model with histone modification-related genes and identification of CAMK2D as a potential response signature to infliximab in ulcerative colitis
BackgroundUlcerative colitis (UC) is a lifelong inflammatory disease affecting the rectum and colon with numerous treatment options that require an individualized treatment plan. Histone modifications regulate chromosome structure and gene expression, resulting in effects on inflammatory and immune...
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Frontiers Media S.A.
2024-01-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1282136/full |
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| author | Shuyu Ye Shuyu Ye Yongqing Lyu Libin Chen Libin Chen Yiwei Wang Yiwei Wang Yue He Yue He Quansi Li Quansi Li Li Tian Li Tian Fen Liu Fen Liu Xiaoyan Wang Xiaoyan Wang Feiyan Ai Feiyan Ai |
| author_facet | Shuyu Ye Shuyu Ye Yongqing Lyu Libin Chen Libin Chen Yiwei Wang Yiwei Wang Yue He Yue He Quansi Li Quansi Li Li Tian Li Tian Fen Liu Fen Liu Xiaoyan Wang Xiaoyan Wang Feiyan Ai Feiyan Ai |
| author_sort | Shuyu Ye |
| collection | DOAJ |
| description | BackgroundUlcerative colitis (UC) is a lifelong inflammatory disease affecting the rectum and colon with numerous treatment options that require an individualized treatment plan. Histone modifications regulate chromosome structure and gene expression, resulting in effects on inflammatory and immune responses. However, the relationship between histone modification-related genes and UC remains unclear.MethodsTranscriptomic data from GSE59071 and GSE66407 were obtained from the Gene Expression Omnibus (GEO), encompassing colonic biopsy expression profiles of UC patients in inflamed and non-inflamed status. Differentially expressed gene (DEG) analyses, functional enrichment analyses, weighted gene co-expression network analysis (WGCNA), and random forest were performed to identify histone modification-related core genes associated with UC inflammation. Features were screened through the least absolute shrinkage and selection operator (LASSO) and support vector machine‐recursive feature elimination (SVM‐RFE), establishing a molecular inflammatory predictive model using logistic regression. The model was validated in the GSE107499 dataset, and the performance of the features was assessed using receiver operating characteristic (ROC) and calibration curves. Immunohistochemistry (IHC) staining of colonic biopsy tissues from UC patients treated with infliximab was used to further confirm the clinical application value. Univariate logistic regression on GSE14580 highlighted features linked to infliximab response.ResultsA total of 253 histone modification-related DEGs were identified between inflammatory and non-inflammatory patients with UC. Seven key genes (IL-1β, MSL3, HDAC7, IRF4, CAMK2D, AUTS2, and PADI2) were selected using WGCNA and random forest. Through univariate logistic regression, three core genes (CAMK2D, AUTS2, and IL-1β) were further incorporated to construct the molecular inflammatory predictive model. The area under the curve (AUC) of the model was 0.943 in the independent validation dataset. A significant association between CAMK2D protein expression and infliximab response was observed, which was validated in another independent verification set of GSE14580 from the GEO database.ConclusionThe molecular inflammatory predictive model based on CAMK2D, AUTS2, and IL-1β could reliably distinguish the mucosal inflammatory status of UC patients. We further revealed that CAMK2D was a predictive marker of infliximab response. These findings are expected to provide a new evidence base for personalized treatment and management strategies for UC patients. |
| first_indexed | 2024-03-08T14:50:52Z |
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| id | doaj.art-104a12af5f8f4d529ab48a7fd99deec1 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-08T14:50:52Z |
| publishDate | 2024-01-01 |
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| series | Frontiers in Immunology |
| spelling | doaj.art-104a12af5f8f4d529ab48a7fd99deec12024-01-11T04:16:06ZengFrontiers Media S.A.Frontiers in Immunology1664-32242024-01-011410.3389/fimmu.2023.12821361282136Construction of a molecular inflammatory predictive model with histone modification-related genes and identification of CAMK2D as a potential response signature to infliximab in ulcerative colitisShuyu Ye0Shuyu Ye1Yongqing Lyu2Libin Chen3Libin Chen4Yiwei Wang5Yiwei Wang6Yue He7Yue He8Quansi Li9Quansi Li10Li Tian11Li Tian12Fen Liu13Fen Liu14Xiaoyan Wang15Xiaoyan Wang16Feiyan Ai17Feiyan Ai18Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, ChinaHunan Key Laboratory of Non-Resolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, ChinaCenter for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, ChinaDepartment of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, ChinaHunan Key Laboratory of Non-Resolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, ChinaXiangya School of Medicine, Central South University, Changsha, Hunan, ChinaDepartment of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, ChinaXiangya School of Medicine, Central South University, Changsha, Hunan, ChinaDepartment of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, ChinaXiangya School of Medicine, Central South University, Changsha, Hunan, ChinaDepartment of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, ChinaHunan Key Laboratory of Non-Resolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, ChinaHunan Key Laboratory of Non-Resolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, ChinaHunan Key Laboratory of Non-Resolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, ChinaHunan Key Laboratory of Non-Resolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, ChinaBackgroundUlcerative colitis (UC) is a lifelong inflammatory disease affecting the rectum and colon with numerous treatment options that require an individualized treatment plan. Histone modifications regulate chromosome structure and gene expression, resulting in effects on inflammatory and immune responses. However, the relationship between histone modification-related genes and UC remains unclear.MethodsTranscriptomic data from GSE59071 and GSE66407 were obtained from the Gene Expression Omnibus (GEO), encompassing colonic biopsy expression profiles of UC patients in inflamed and non-inflamed status. Differentially expressed gene (DEG) analyses, functional enrichment analyses, weighted gene co-expression network analysis (WGCNA), and random forest were performed to identify histone modification-related core genes associated with UC inflammation. Features were screened through the least absolute shrinkage and selection operator (LASSO) and support vector machine‐recursive feature elimination (SVM‐RFE), establishing a molecular inflammatory predictive model using logistic regression. The model was validated in the GSE107499 dataset, and the performance of the features was assessed using receiver operating characteristic (ROC) and calibration curves. Immunohistochemistry (IHC) staining of colonic biopsy tissues from UC patients treated with infliximab was used to further confirm the clinical application value. Univariate logistic regression on GSE14580 highlighted features linked to infliximab response.ResultsA total of 253 histone modification-related DEGs were identified between inflammatory and non-inflammatory patients with UC. Seven key genes (IL-1β, MSL3, HDAC7, IRF4, CAMK2D, AUTS2, and PADI2) were selected using WGCNA and random forest. Through univariate logistic regression, three core genes (CAMK2D, AUTS2, and IL-1β) were further incorporated to construct the molecular inflammatory predictive model. The area under the curve (AUC) of the model was 0.943 in the independent validation dataset. A significant association between CAMK2D protein expression and infliximab response was observed, which was validated in another independent verification set of GSE14580 from the GEO database.ConclusionThe molecular inflammatory predictive model based on CAMK2D, AUTS2, and IL-1β could reliably distinguish the mucosal inflammatory status of UC patients. We further revealed that CAMK2D was a predictive marker of infliximab response. These findings are expected to provide a new evidence base for personalized treatment and management strategies for UC patients.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1282136/fullhistone modificationulcerative colitismolecular inflammatory predictive modelinfliximab responseCAMK2D |
| spellingShingle | Shuyu Ye Shuyu Ye Yongqing Lyu Libin Chen Libin Chen Yiwei Wang Yiwei Wang Yue He Yue He Quansi Li Quansi Li Li Tian Li Tian Fen Liu Fen Liu Xiaoyan Wang Xiaoyan Wang Feiyan Ai Feiyan Ai Construction of a molecular inflammatory predictive model with histone modification-related genes and identification of CAMK2D as a potential response signature to infliximab in ulcerative colitis Frontiers in Immunology histone modification ulcerative colitis molecular inflammatory predictive model infliximab response CAMK2D |
| title | Construction of a molecular inflammatory predictive model with histone modification-related genes and identification of CAMK2D as a potential response signature to infliximab in ulcerative colitis |
| title_full | Construction of a molecular inflammatory predictive model with histone modification-related genes and identification of CAMK2D as a potential response signature to infliximab in ulcerative colitis |
| title_fullStr | Construction of a molecular inflammatory predictive model with histone modification-related genes and identification of CAMK2D as a potential response signature to infliximab in ulcerative colitis |
| title_full_unstemmed | Construction of a molecular inflammatory predictive model with histone modification-related genes and identification of CAMK2D as a potential response signature to infliximab in ulcerative colitis |
| title_short | Construction of a molecular inflammatory predictive model with histone modification-related genes and identification of CAMK2D as a potential response signature to infliximab in ulcerative colitis |
| title_sort | construction of a molecular inflammatory predictive model with histone modification related genes and identification of camk2d as a potential response signature to infliximab in ulcerative colitis |
| topic | histone modification ulcerative colitis molecular inflammatory predictive model infliximab response CAMK2D |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1282136/full |
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