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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 盧子彬(Tzu-Pin Lu),李永凌(Yungling L. Lee) | |
| dc.contributor.author | Ching-Hui Tsai | en |
| dc.contributor.author | 蔡靜慧 | zh_TW |
| dc.date.accessioned | 2021-06-16T10:37:24Z | - |
| dc.date.available | 2020-08-27 | |
| dc.date.copyright | 2020-08-27 | |
| dc.date.issued | 2020 | |
| dc.date.submitted | 2020-07-02 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/60938 | - |
| dc.description.abstract | 背景及目的： 呼吸道融合病毒(Respiratory syncytial virus, RSV)是造成人類呼吸道感染的主因，並且與氣喘發作有關。然而，並非所有氣喘孩童在感染RSV後，均會發生氣喘發作的症狀，孩童本身的基因對氣喘發作嚴重程度也有貢獻。因此，本研究目的將結合RSV感染、全基因體基因表現及全基因體基因型資料，探討影響氣喘發作的標的基因。 方法： 以Gene Expression Omnibus (GEO)資料庫進行RSV感染的轉錄體資料的統合分析，討論RSV感染的顯著基因及生物路徑，以數量性狀基因座(expression quantitative trait loci, eQTL)分析，搜尋潛在影響RSV感染顯著基因的單一核苷酸多型性(single nucleotide polymorphisms, SNPs)，於台灣孩童氣喘研究聯盟(Taiwanese Consortium of Childhood Asthma Study, TCCAS)中，利用以基因為基礎的邏輯式回歸篩選氣喘發作的基因，並於獨立族群(Childhood Asthma Management Program, CAMP)驗證，最後進行基因、RSV感染與氣喘發作的交互作用分析。 結果： 利用RSV感染的轉錄體資料進行統合分析後，發現352個顯著表現基因(FDR<0.05)。利用38,123個SNPs進行與氣喘發作的相關性分析，我們發現11個SNPs位於GADD45A、GYPB、MS4A3、NFE2、RNASE3、EPB41L3、CEACAM6及CEACAM3等8個基因與氣喘發作有顯著相關(FDR<0.05)，並也經過獨立族群驗證，其中rs7251960 (CEACAM3)會修飾RSV感染對氣喘發作的風險(p for interaction <0.05)。在肺部組織中，rs7251960的核苷酸變異與CEACAM3 基因表達量有顯著相關(p for trend=1.2×10-7)。利用兩個獨立的族群資料分析，發現相對於非氣喘發作者，氣喘發作者的鼻腔黏膜CEACAM3 基因表現量較低。 結論： GADD45A、GYPB、MS4A3、NFE2、RNASE3、EPB41L3、CEACAM6及CEACAM3是影響氣喘發作的基因。rs7251960是影響CEACAM3基因表現的數量性狀基因座，且CEACAM3 基因表現量與氣喘發作有顯著相關，CEACAM3可修飾RSV潛在感染對於氣喘發作的影響。 | zh_TW |
| dc.description.abstract | Background: Respiratory syncytial virus (RSV) is a major cause of human respiratory infections and is associated with asthma exacerbations, the symptoms of which include nocturnal wheezing and severe wheezing causing limited speech. Nevertheless, not all children exposed to RSV develop asthma symptoms, possibly because genes modulate the effects of RSV on asthma exacerbations. Objective: The purpose of this study was to identify genes that modulate the effect of RSV latent infection on asthma exacerbations on a genome-wide scale. Methods: We performed an in silico meta-analysis to investigate differentially expressed genes (DEGs) of RSV infection from Gene Expression Omnibus (GEO) datasets. Expression quantitative trait loci (eQTL) methods were applied to select single nucleotide polymorphisms (SNPs) that were associated with DEGs. SNPs located in the gene range ± 5 kb were included. Gene-based analysis was used to identify SNPs that were significantly associated with asthma exacerbations in the Taiwanese Consortium of Childhood Asthma Study (TCCAS) and validation was attempted in an independent cohort, the Childhood Asthma Management Program (CAMP). Gene-RSV interaction analyses were performed to investigate the association between the interaction of SNPs and RSV latent infection on asthma exacerbations. Results: A total of 352 significant DEGs were found by meta-analysis of RSV-related genes. We used 38,123 SNPs related to DEGs to investigate the genetic main effects on asthma exacerbations. We found that eight RSV-related genes (GADD45A, GYPB, MS4A3, NFE2, RNASE3, EPB41L3, CEACAM6 and CEACAM3) were significantly associated with asthma exacerbations in TCCAS and also validated in CAMP. In TCCAS, rs7251960 (CEACAM3) significantly modulated the effect of RSV latent infection on asthma exacerbations (FDR<0.05). The rs7251960 variants were associated with CEACAM3 mRNA expression in lung tissue (p for trend=1.2×10-7). CEACAM3 mRNA was reduced in nasal mucosa from subjects with asthma exacerbations in two independent datasets. Conclusion: GADD45A, GYPB, MS4A3, NFE2, RNASE3, EPB41L3, CEACAM6 and CEACAM3 are potential markers of asthma exacerbations. rs7251960 is an eQTL for CEACAM3, and CEACAM3 mRNA expression is reduced in subjects experiencing asthma exacerbations. CEACAM3 may be a modulator of RSV latent infection on asthma exacerbations. | en |
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| dc.description.tableofcontents | 口試委員會審定書 ii 致謝…………… iii 中文摘要 iv Abstract vi 1. Introduction 1 1.1 Importance of asthma in children 1 1.2 Genetic susceptibility to asthma and asthma exacerbations in children 1 1.3 Epidemiology of respiratory syncytial virus (RSV) 4 1.4 RSV infection and asthma and asthma exacerbations 4 1.5 RSV infection related genes 5 1.6 Significance of gene-RSV interaction analysis in asthma exacerbations 7 2. Study objectives 10 3. Study flowchart 13 4. Materials and Methods 14 4.1 Target genes and SNPs selection 14 4.1.1 Meta-analysis of RSV-related genes 14 4.1.2 Expression Quantitative Trait Loci (eQTL) analysis and SNPs identification 16 4.2 Study population 16 4.3 DNA preparation and genotyping 17 4.4 RSV latent infection measurement 17 4.5 Definition of asthma outcomes 18 4.6 Independent cohort 19 4.7 Statistical analyses 19 4.8 eQTL, mRNA analyses and ENCODE analysis of target SNPs 21 5. Results 22 5.1 Meta-analysis of RSV infection transcriptomics 23 5.2 RSV-related SNPs identification 27 5.3 Clinical characteristics of study populations 27 5.4 Genetic main effects on asthma exacerbations 28 5.5 CEACAM3 modulates the effects of RSV latent infection on asthma exacerbations 32 5.6 CEACAM3 and RSV latent infection on pulmonary function 33 5.7 rs7251960, CEACAM3 and asthma exacerbations 35 5.8 Potentially biological regulatory of rs7251960 in CEACAM3 36 6. Discussion 39 6.1 Summary 39 6.2 CEACAM3 associated with asthma or RSV 39 6.3 CEACAM3 associated regulatory genes of RSV and asthma 40 6.4 Other genes associated with asthma or RSV 42 6.5 Validation 43 6.6 Strengths 44 6.7 Limitations 45 6.8 Conclusions 46 7. References 47 圖目錄Listing of figures Figure 1. Word cloud consisting of asthma-related genes from meta-analyses of asthma genome-wide association studies. 2 Figure 2. Gene-environment interactions in heterogeneity and severity of asthma 3 Figure 3. Candidate genes associated with severe RSV infection and asthma 8 Figure 4. Schema of omics technologies and their corresponding analysis targets. 9 Figure 5. Flowchart of the study 13 Figure 6. Flow chart showing study design and results. 22 Figure 7. Volcano plot of RSV-related genes for meta-analysis. 24 Figure 8. Difference of gene expression between RSV infection acute phase and recovery phase/healthy controls. 25 Figure 9. Canonical pathways of RSV-related differentially expressed genes by IPA. 26 Figure 10. Joint effects of CEACAM3 SNP genotypes and RSV infection on asthma exacerbations in TCCAS cohort. 32 Figure 11. rs7251960 is an eQTL for CEACAM3 in lung tissue and whole blood, and CEACAM3 mRNA expression is reduced in the nasal mucosa of subjects with asthma exacerbations. 35 Figure 12. Summary of CEACAM3 and associated regulatory genes of RSV and asthma. 41 Figure 13. LD plots of SNPs in CEACAM3 gene 43 表目錄 Listing of tables Table 1. Published genome-wide gene expression papers related to RSV infection in human studies 6 Table 2. Genome-wide gene expression studies from human peripheral blood related to RSV infection 23 Table 3. Clinical characteristics of TCCAS and CAMP 27 Table 4. Gene-based main effects of SNPs on asthma exacerbations 29 Table 5. Results of analyses of genetic association and interaction of SNPs on asthma exacerbations 30 Table 6. Summary of rs7251960 and RSV latent infection on pulmonary function variables 34 Table 7. ENCODE analysis of rs7251960 potential regulatory mechanisms underlying eQTL for CEACAM3 37 Table 8. DeepSEA analyses of rs7251960 in CEACAM3 identify top 10 potential alterations (sorted by E-value) in transcription factor activities 38 Table 9. The associations between asthma exacerbations and other asthma outcomes 46 附錄 (Supplementary) 53 1. Materials and methods 53 1.1 RankProd method 53 1.2 Expression quantitative trait loci analysis 53 1.3 Removal anti-human IgG from sera or plasma sample 54 1.4 eQTL of CEACAM3 mRNA expression 55 1.5 mRNA analyses in asthmatic subjects from GEO datasets 56 2. Supplement tables 58 Table S1. Up-regulated differentially expressed genes in the meta-analysis of RSV infection 58 Table S2. Down-regulated differentially expressed genes in the meta-analysis of RSV infection 71 Table S3. Genetic main effects of SNPs with asthma exacerbations in TCCAS and CAMP, by additive genetic model 73 Table S4. Genetic main effects of SNPs with asthma exacerbations in TCCAS and CAMP, by dominant genetic model 79 | |
| dc.language.iso | en | |
| dc.subject | 氣喘 | zh_TW |
| dc.subject | 孩童 | zh_TW |
| dc.subject | 統合分析 | zh_TW |
| dc.subject | 基因環境交互作用 | zh_TW |
| dc.subject | 整合式分析 | zh_TW |
| dc.subject | children | en |
| dc.subject | asthma | en |
| dc.subject | meta-analysis | en |
| dc.subject | integrative analysis | en |
| dc.subject | gene-environment interaction | en |
| dc.title | 以全基因轉錄體及基因環境交互作用探討RSV對氣喘發作的影響 | zh_TW |
| dc.title | Genome-wide integrative analysis to identify genetic targets for RSV latent infection on asthma exacerbations | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 108-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.author-orcid | 0000-0003-0998-8230 | |
| dc.contributor.oralexamcommittee | 江伯倫(Bor-Luen Chiang),張雅貞(Ya-Jen Chang),沈志陽(Chen-Yang Shen) | |
| dc.subject.keyword | 孩童,氣喘,統合分析,整合式分析,基因環境交互作用, | zh_TW |
| dc.subject.keyword | children,asthma,meta-analysis,integrative analysis,gene-environment interaction, | en |
| dc.relation.page | 81 | |
| dc.identifier.doi | 10.6342/NTU202001249 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2020-07-02 | |
| dc.contributor.author-college | 公共衛生學院 | zh_TW |
| dc.contributor.author-dept | 流行病學與預防醫學研究所 | zh_TW |
| 顯示於系所單位： | 流行病學與預防醫學研究所 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| U0001-0107202016223200.pdf 未授權公開取用 | 10.97 MB | Adobe PDF |
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