An integrative analysis of single-cell and bulk transcriptome and bidirectional mendelian randomization analysis identified C1Q as a novel stimulated risk gene for Atherosclerosis
BackgroundThe role of complement component 1q (C1Q) related genes on human atherosclerotic plaques (HAP) is less known. Our aim is to establish C1Q associated hub genes using single-cell RNA sequencing (scRNA-seq) and bulk RNA analysis to diagnose and predict HAP patients more effectively and invest...
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| Format: | Article |
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Frontiers Media S.A.
2023-12-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1289223/full |
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| author | Hong-Kai Cui Chao-Jie Tang Yu Gao Zi-Ang Li Jian Zhang Yong-Dong Li Yong-Dong Li |
| author_facet | Hong-Kai Cui Chao-Jie Tang Yu Gao Zi-Ang Li Jian Zhang Yong-Dong Li Yong-Dong Li |
| author_sort | Hong-Kai Cui |
| collection | DOAJ |
| description | BackgroundThe role of complement component 1q (C1Q) related genes on human atherosclerotic plaques (HAP) is less known. Our aim is to establish C1Q associated hub genes using single-cell RNA sequencing (scRNA-seq) and bulk RNA analysis to diagnose and predict HAP patients more effectively and investigate the association between C1Q and HAP (ischemic stroke) using bidirectional Mendelian randomization (MR) analysis.MethodsHAP scRNA-seq and bulk-RNA data were download from the Gene Expression Omnibus (GEO) database. The C1Q-related hub genes was screened using the GBM, LASSO and XGBoost algorithms. We built machine learning models to diagnose and distinguish between types of atherosclerosis using generalized linear models and receiver operating characteristics (ROC) analyses. Further, we scored the HALLMARK_COMPLEMENT signaling pathway using ssGSEA and confirmed hub gene expression through qRT-PCR in RAW264.7 macrophages and apoE-/- mice. Furthermore, the risk association between C1Q and HAP was assessed through bidirectional MR analysis, with C1Q as exposure and ischemic stroke (IS, large artery atherosclerosis) as outcomes. Inverse variance weighting (IVW) was used as the main method.ResultsWe utilized scRNA-seq dataset (GSE159677) to identify 24 cell clusters and 12 cell types, and revealed seven C1Q associated DEGs in both the scRNA-seq and GEO datasets. We then used GBM, LASSO and XGBoost to select C1QA and C1QC from the seven DEGs. Our findings indicated that both training and validation cohorts had satisfactory diagnostic accuracy for identifying patients with HPAs. Additionally, we confirmed SPI1 as a potential TF responsible for regulating the two hub genes in HAP. Our analysis further revealed that the HALLMARK_COMPLEMENT signaling pathway was correlated and activated with C1QA and C1QC. We confirmed high expression levels of C1QA, C1QC and SPI1 in ox-LDL-treated RAW264.7 macrophages and apoE-/- mice using qPCR. The results of MR indicated that there was a positive association between the genetic risk of C1Q and IS, as evidenced by an odds ratio (OR) of 1.118 (95%CI: 1.013–1.234, P = 0.027).ConclusionThe authors have effectively developed and validated a novel diagnostic signature comprising two genes for HAP, while MR analysis has provided evidence supporting a favorable association of C1Q on IS. |
| first_indexed | 2024-03-08T21:32:49Z |
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| id | doaj.art-09757d417c044b67b81100e5e9c007bf |
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| language | English |
| last_indexed | 2024-03-08T21:32:49Z |
| publishDate | 2023-12-01 |
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| spelling | doaj.art-09757d417c044b67b81100e5e9c007bf2023-12-21T04:17:59ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-12-011410.3389/fimmu.2023.12892231289223An integrative analysis of single-cell and bulk transcriptome and bidirectional mendelian randomization analysis identified C1Q as a novel stimulated risk gene for AtherosclerosisHong-Kai Cui0Chao-Jie Tang1Yu Gao2Zi-Ang Li3Jian Zhang4Yong-Dong Li5Yong-Dong Li6Department of Neurological Intervention, The First Affiliated Hospital, Xinxiang Medical University, Xinxiang, Henan, ChinaInstitute of Diagnostic and Interventional Radiology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Neurological Intervention, The First Affiliated Hospital, Xinxiang Medical University, Xinxiang, Henan, ChinaDepartment of Neurological Intervention, The First Affiliated Hospital, Xinxiang Medical University, Xinxiang, Henan, ChinaDepartment of Neurological Intervention, The First Affiliated Hospital, Xinxiang Medical University, Xinxiang, Henan, ChinaDepartment of Neurological Intervention, The First Affiliated Hospital, Xinxiang Medical University, Xinxiang, Henan, ChinaInstitute of Diagnostic and Interventional Radiology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaBackgroundThe role of complement component 1q (C1Q) related genes on human atherosclerotic plaques (HAP) is less known. Our aim is to establish C1Q associated hub genes using single-cell RNA sequencing (scRNA-seq) and bulk RNA analysis to diagnose and predict HAP patients more effectively and investigate the association between C1Q and HAP (ischemic stroke) using bidirectional Mendelian randomization (MR) analysis.MethodsHAP scRNA-seq and bulk-RNA data were download from the Gene Expression Omnibus (GEO) database. The C1Q-related hub genes was screened using the GBM, LASSO and XGBoost algorithms. We built machine learning models to diagnose and distinguish between types of atherosclerosis using generalized linear models and receiver operating characteristics (ROC) analyses. Further, we scored the HALLMARK_COMPLEMENT signaling pathway using ssGSEA and confirmed hub gene expression through qRT-PCR in RAW264.7 macrophages and apoE-/- mice. Furthermore, the risk association between C1Q and HAP was assessed through bidirectional MR analysis, with C1Q as exposure and ischemic stroke (IS, large artery atherosclerosis) as outcomes. Inverse variance weighting (IVW) was used as the main method.ResultsWe utilized scRNA-seq dataset (GSE159677) to identify 24 cell clusters and 12 cell types, and revealed seven C1Q associated DEGs in both the scRNA-seq and GEO datasets. We then used GBM, LASSO and XGBoost to select C1QA and C1QC from the seven DEGs. Our findings indicated that both training and validation cohorts had satisfactory diagnostic accuracy for identifying patients with HPAs. Additionally, we confirmed SPI1 as a potential TF responsible for regulating the two hub genes in HAP. Our analysis further revealed that the HALLMARK_COMPLEMENT signaling pathway was correlated and activated with C1QA and C1QC. We confirmed high expression levels of C1QA, C1QC and SPI1 in ox-LDL-treated RAW264.7 macrophages and apoE-/- mice using qPCR. The results of MR indicated that there was a positive association between the genetic risk of C1Q and IS, as evidenced by an odds ratio (OR) of 1.118 (95%CI: 1.013–1.234, P = 0.027).ConclusionThe authors have effectively developed and validated a novel diagnostic signature comprising two genes for HAP, while MR analysis has provided evidence supporting a favorable association of C1Q on IS.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1289223/fullatherosclerotic plaque (AP)ScRNA-seqMendelian randomization (MR)complement component 1q (C1q)LASSO |
| spellingShingle | Hong-Kai Cui Chao-Jie Tang Yu Gao Zi-Ang Li Jian Zhang Yong-Dong Li Yong-Dong Li An integrative analysis of single-cell and bulk transcriptome and bidirectional mendelian randomization analysis identified C1Q as a novel stimulated risk gene for Atherosclerosis Frontiers in Immunology atherosclerotic plaque (AP) ScRNA-seq Mendelian randomization (MR) complement component 1q (C1q) LASSO |
| title | An integrative analysis of single-cell and bulk transcriptome and bidirectional mendelian randomization analysis identified C1Q as a novel stimulated risk gene for Atherosclerosis |
| title_full | An integrative analysis of single-cell and bulk transcriptome and bidirectional mendelian randomization analysis identified C1Q as a novel stimulated risk gene for Atherosclerosis |
| title_fullStr | An integrative analysis of single-cell and bulk transcriptome and bidirectional mendelian randomization analysis identified C1Q as a novel stimulated risk gene for Atherosclerosis |
| title_full_unstemmed | An integrative analysis of single-cell and bulk transcriptome and bidirectional mendelian randomization analysis identified C1Q as a novel stimulated risk gene for Atherosclerosis |
| title_short | An integrative analysis of single-cell and bulk transcriptome and bidirectional mendelian randomization analysis identified C1Q as a novel stimulated risk gene for Atherosclerosis |
| title_sort | integrative analysis of single cell and bulk transcriptome and bidirectional mendelian randomization analysis identified c1q as a novel stimulated risk gene for atherosclerosis |
| topic | atherosclerotic plaque (AP) ScRNA-seq Mendelian randomization (MR) complement component 1q (C1q) LASSO |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1289223/full |
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