博碩士論文 101284004 詳細資訊




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姓名 李世偉(Shih-Wei Lee)  查詢紙本館藏   畢業系所 生命科學系
論文名稱 在台灣結核病中細胞激素訊息抑制子表現和基因多型性的研究
(Studies on suppressor of cytokine signaling (SOCS) expression and gene polymorphism in the Taiwanese tuberculosis)
檔案 [Endnote RIS 格式]    [Bibtex 格式]    至系統瀏覽論文 (2021-11-21以後開放)
摘要(中) 結核病(TB)是由結核分枝桿菌感染所引起,目前仍然是引領全球公共衛生問題與傳染病造成死亡的起因。細胞激素訊息抑制子(SOCS)和基因單核苷酸多型性(SNP)分別在抵抗微生物感染和對結核病易感性上扮演重要的角色。然而,沒有研究去證實是否在八個SOCS家族中,任一成員是否與台灣結核病有密切的關聯性,以及是否SOCS-3、干擾素γ、維生素D受體(VDR)、維生素D結合蛋白(VDBP)與SNP rs4331426的基因多型性與結核病感染風險有關。本論文的總目標在探討八個SOCS家族成員的表達譜,以及SOCS-3、IFNγ、VDR、VDBP和rs4331426等基因的單核苷酸多型性分別與肺結核的關聯性。第一章發現在活動性結核病與健康受試者之間, SOCS基因的表現會因性別與年齡而有所差異,以及一些特定的SOCS成員,尤其是SOCS-3,允許從健康和潛伏性結核感染者中區分出活動性結核病患者。第二章發現SOCS-3的SNP rs8064821的基因型頻率,在女性結核病患者與非結核病患者之間有顯著的差異發生,但在男性則沒有。此發現可能有助於解釋男女性結核病受試者之間SOCS-3 mRNA表現水平的差異。第三章發現IFN-γ基因多型性,尤其是rs1861494、rs2069718和rs2430561,在台灣漢族人口中對結核病易感性是有所關連性。第四章發現VDR和VDBP單核苷酸多型性在台灣漢族人口與結核病易感性有相關性。第五章發現SNP rs4331426與台灣漢族女性對結核病易感性有關聯性。這項研究結果會使我們更了解在台灣患者中,基因的風險因子與結核病易感性之間的關聯性,以及找到可用於從潛伏性結核感染者和健康受試者中去區分活動性結核病患者的生物標誌基因。
摘要(英) Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains a leading public health problem worldwide and causes of death from infectious disease. Suppressors of cytokine signaling (SOCS) and gene single nucleotide polymorphisms (SNPs) play important roles in the protection against microbial infection and susceptibility to TB, respectively. However, no studies have demonstrated whether any of the eight SOCS family members are closely associated with TB in Taiwan and whether gene polymorphisms of SOCS-3, interferon gamma (IFNγ), SNP rs4331426, vitamin D receptor (VDR), and vitamin D binding protein (VDBP) are associated with the risk of TB. The overall objective of this dissertation was designed to examine the expression profiles of the eight SOCS families, as well as SNPs of SOCS-3, IFNγ, rs4331426, VDR, and VDBP, in association with tuberculosis. Chapter One discovered that SOCS gene expresses differently between active TB and healthy subjects with gender and age dependencies and that particular SOCS families, especially SOCS-3, allow discrimination of active TB from healthy and LTBI subjects. Chapter Two discovered that significant difference in genotype frequency for SOCS-3 SNP rs8064821 occurred between TB and non-TB groups of women but not men, and such findings may help explain the difference of SOCS-3 mRNA levels between male and female TB subjects. Chapter Three discovered that IFN-γ gene polymorphisms, particularly rs1861494, rs2069718, and rs2430561, were associated with susceptibility to tuberculosis in a Han Taiwanese population. Chapter Four discovered that VDR and VDBP SNPs were associated with susceptibility to tuberculosis in a Han Taiwanese population. Chapter Five discovered that SNP rs4331426 was associated with female but not with male TB in the Han Taiwanese population. Results of these studies lead us to be better understanding of the association between genetic risk factors and susceptibility to TB disease in Taiwan patients, as well as finding a biomarker for distinguishing active TB from LTBI and healthy subjects.
關鍵字(中) ★ 結核病
★ 單核酸多型性
★ 細胞激素訊息抑制者
★ 干擾素-γ
★ 維生素D受體
★ 維生素D結合蛋白
關鍵字(英) ★ Tuberculosis
★ Single-nucleotide polymorphism
★ suppressor of cytokine signaling
★ Interferon gamma
★ vitamin D receptor
★ vitamin D binding protein
論文目次 Chinese Abstract ......................................i
English Abstract ......................................ii
Declarations ......................................iii
Acknowledgments ......................................iv
Table of Contents......................................v
List of Tables ......................................viii
List of Figures ......................................ix
Abbreviations ......................................x

1. Chapter One Suppressors of cytokine signaling in
the Taiwanese tuberculosis..........................1
1-1. Introduction...................................3
1-2. Materials and methods..........................4
1-2.1. Clinical sample collection.....................4
1.2.2. RNA isolation..................................5
1-2.3. Real-time polymerase chain reaction (real-time
PCR) for SOCS mRNA.............................5
1-2.4. Statistical analysis...........................6
1-3. Results and discussion.........................6
1-4. Conclusions....................................12
1-5. References.....................................13
Tables 1-1~2..........................................17
Figures 1-1~5..........................................19

2. Chapter Two SOCS-3 gene polymorphisms associated
with susceptibility to tuberculosis in the Taiwanese
population..........................................28
2-1. Introduction...................................30
2-2. Materials and methods..........................31
2-2.1. Study population...............................31
2-2.2. DNA extraction.................................32
2-2.3. SNP genotyping assays..........................32
2-2.4. Statistical analysis...........................33
2-3. Results and discussion.........................33
2-3.1. Demographic information of the study subjects..33
2-3.2. SNPs of SOCS-3 are associated with susceptibility
to tuberculosis................................33
2-4. Conclusions....................................36
2-5. References.....................................37
Tables 2-1~5..........................................41

3. Chapter Three Interferon gamma polymorphisms associated
with susceptibility to tuberculosis in a Han Taiwanese
population..........................................47
3-1. Introduction...................................49
3-2. Materials and methods..........................50
3-2.1. Study population...............................50
3.2.2. DNA extraction and genotyping of the SNPs......50
3-2.3. Statistical analysis...........................51
3-3. Results........................................52
3-3.1. Demographic information of the study subjects..52
3-3.2. SNPs of IFN-γ are associated with susceptibility
to tuberculosisv...............................52
3-4. Discussion and conclusions.....................53
3-5. References.....................................54
Tables 3-1~3..........................................57
Figure 3-1............................................60

4. Chapter Four VDR and VDBP genes polymorphisms associated
with susceptibility to tuberculosis in a Han Taiwanese
population..........................................61
4-1. Introduction...................................63
4-2. Materials and methods..........................64
4-2.1. Participants...................................64
4-2.2. DNA preparation................................65
4-2.3. Single nucleotide polymorphism genotyping......65
4-2.4. Statistical analysis...........................66
4-3. Results........................................66
4-2.1. Demographic information of the study
participants...................................66
4-2.2. VDR and VDBP variant(s) associated with
susceptibility to tuberculosis.................66
4-4. Discussion and conclusions.....................67
4-5. References.....................................69
Tables 4-1~4..........................................75

5. Chapter Five SNP rs4331426 in 18q11.2 is associated
with susceptibility to tuberculosis among female Han
Taiwanese...........................................79
5-1. Introduction...................................81
5-2. Materials and methods..........................82
5-2.1. Subjects.......................................82
5-2.2. DNA preparation................................82
5-2.3. SNP genotyping.................................82
5-2.4. Statistical analysis...........................83
5-3. Results........................................83
5-3.1. Demographic information of the study subjects..83
5-3.2. The SNP rs4331426 associated with susceptibility
to tuberculosis................................83
5-4. Discussion and conclusions.....................84
5-5. References.....................................85
Table 5-1............................................87
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Chapter five:
1.Comstock GW. Tuberculosis in twins: a re-analysis of the Prophit survey. Am Rev Respir Dis 1978; 117: 621-624.
2.Mahasirimongkol S, Yanai H, Nishida N, Ridruechai C, Matsushita I, Ohashi J, et al. Genome-wide SNP-based linkage analysis of tuberculosis in Thais. Genes Immun 2009; 10: 77-83.
3.Miller EN, Jamieson SE, Joberty C, Fakiola M, Hudson D, Peacock CS, et al. Genome-wide scans for leprosy and tuberculosis susceptibility genes in Brazilians. Genes Immun 2004; 5: 63-67.
4.Jamieson SE, Miller EN, Black GF, Peacock CS, Cordell HJ, Howson JM, et al. Evidence for a cluster of genes on chromosome 17q11-q21 controlling susceptibility to tuberculosis and leprosy in Brazilians. Genes Immun 2004; 5: 46-57.
5.Thye T, Vannberg FO, Wong SH, Owusu-Dabo E, Osei I, Gyapong J, et al. Genome-wide association analyses identifies a susceptibility locus for tuberculosis on chromosome 18q11.2. Nat Genet 2010; 42: 739-741.
6.Taiwan Tuberculosis Control Report 2012. Centers for Disease Control, Department of Health, R.O.C. (Taiwan).
7.Qu HQ, Fisher-Hoch SP, McCormick JB. Knowledge gaining by human genetic studies on tuberculosis susceptibility. J Hum Genet 2011; 56: 177-182.
8.Hsu YH, Chen CW, Sun HS, Jou R, Lee JJ, Su IJ. Association of NRAMP 1 gene polymorphism with susceptibility to tuberculosis in Taiwanese aboriginals. J Formos Med Assoc 2006; 105: 363-369.
9.Dai Y, Zhang X, Pan H, Tang S, Shen H, Wang J. Fine mapping of genetic polymorphisms of pulmonary tuberculosis within chromosome 18q11.2 in the Chinese population: a case-control study. BMC Infect Dis 2011; 11: 282.
10.El Gammal AT, Bru¨chmann M, Zustin J, Isbarn H, Hellwinkel OJ, Ko¨llermann J, et al. Chromosome 8p deletions and 8q gains are associated with tumor progression and poor prognosis in prostate cancer. Clin Cancer Res 2010; 16: 56-64.
指導教授 高永旭 褚志斌(Yung-Hsi Kao Chih-Pin Chuu) 審核日期 2016-11-25
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