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

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李世偉(Shih-Wei Lee) 查詢紙本館藏

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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)

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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

參考文獻

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Chapter four:
1.World Health Organization (WHO). Global Tuberculosis Report 2013. Geneva, 2013. Available at: http://www.who.int/iris/bitstream/10665/91355/1/9789241564 656 eng.pdf?ua=1
2.Hsu YH, Chen CW, Sun HS, Jou R, Lee, IJ, Su IJ. Association of NRAMP 1 gene polymorphism with susceptibility to tuberculosis in Taiwanese aboriginals. J Formos Med Assoc 2006; 105: 363–369.
3.Lee SW, Chuang TY, Huang HH, Lee KF, Chen TT, Kao YH, et al. Interferon gamma polymorphisms associated with susceptibility to tuberculosis in a Han Taiwanese population. J Microbiol Immunol Infect 2015; 48: 376-380.
4.Kliewer SA, Umesono K, Mangelsdorf DJ, Evans RM. Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signaling. Nature 1992; 355: 446-449.
5.Lemire JM. Immunomodulatory actions of 1,25-dihydroxyvitamin D3. J Steroid Biochem Mol Biol 1995; 53: 599-602.
6.Imazeki I, Matsuzaki J, Tsuji K, Nishimura T. Immunomodulating effect of vitamin D3 derivatives on type-1 cellular immunity. Biomed Res 2006; 27: 1-9.
7.Deluca HF, Cantorna MT. Vitamin D: its role and uses in immunology. FASEB J 2001; 15: 2579-2585.
8.Leung KH. Inhibition of human natural killer cell and lymphokine-activated killer cell cytotoxicity and differentiation by vitamin D3. Scand J Immunol 1989; 30: 199-208.
9.Rook GA, Steele J, Fraher L, Barker S, Karmali R, O′Riordan J, et al. Vitamin D3, gamma interferon, and control of proliferation of Mycobacterium tuberculosis by human monocytes. Immunology 1986; 57: 159-163.
10.Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 2006; 311: 1770-1773.
11.Martineau AR, Wilkinson KA, Newton SM, Floto RA, Norman AW, Skolimowska K, et al. IFN-gamma- and TNF-independent vitamin D-inducible human suppression of mycobacteria: the role of cathelicidin LL-37. J Immunol 2007; 178: 7190-7198.
12.Selvaraj P, Narayanan PR, Reetha AM. Association of vitamin D receptor genotypes with the susceptibility to pulmonary tuberculosis in female patients and resistance in female contacts. Indian J Med Res 2000; 111: 172–179.
13.Bornman L, Campbell SJ, Fielding K, Bah B, Sillah J, Gustafson P, et al. Vitamin D receptor polymorphisms and susceptibility to tuberculosis in west Africa: a case-control and family study. J Infect Dis 2004; 190: 1631–1641.
14.Lewis SJ, Baker I, Davey SG. Meta-analysis of vitamin D receptor polymorphisms and pulmonary tuberculosis risk. Int J Tuberc Lung Dis 2005; 9: 1174-1177.
15.Wilkinson RJ, Llewelyn M, Toossi Z, Patel P, Pasvol G, Lalvani A, et al. Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London: a case control study. Lancet 2000; 355: 618–621.
16.Fitness J, Floyd S, Warndorff DK, Sichali L, Malema S, Crampin AC, et al. Large-scale candidate gene study of tuberculosis susceptibility in the Karonga district of northern Malawi. Am J Trop Med Hyg 2004; 71: 341-349.
17.Banoei MM, Mirsaeidi MS, Houshmand M, Tabarsi P, Ebrahimi G, Zargari L, et al. Vitamin D receptor homozygote mutant tt and bb are associated with susceptibility to pulmonary tuberculosis in the Iranian population. Int J Infect Dis 2010; 14: e84-85.
18.Bellamy R, Ruwende C, Corrah T. Tuberculosis and chronic hepatitis B virus infection in Africans and variation in the vitamin D receptor. J Infect Dis 1999; 179: 721-724.
19.Cleve H, Constans J. The mutants of the vitamin-D-binding protein: more than120 variants of the GC/DBP system. Vox Sang 1988; 54: 215-225.
20.Arnaud J, Constans J. Affinity differences for vitamin D metabolites associated with the genetic isoforms of the human serum carrier protein (DBP). Hum Genet 1993; 92: 183-188.
21.Lauridsen AL, Vestergaard P, Hermann AP, Brot C, Heickendorff L, Mosekilde L, et al. Plasma concentrations of 25-hydroxy-vitamin D and 1,25-dihydroxy-vitamin D are related to the phenotype of Gc (vitamin D-binding protein): a cross-sectional study on 595 early postmenopausal women. Calcif Tissue Int 2005; 77: 15-22.
22.Abbas S, Linseisen J, Slanger T, Kropp S, Mutschelknauss EJ, Flesch-Janys D, et al. The Gc2 allele of the vitamin D binding protein is associated with a decreased postmenopausal breast cancer risk, independent of the vitamin d status. Cancer Epidemiol Biomarkers Prev 2008; 17: 1339-1343.
23.Martineau AR, Leandro AC, Anderson ST, Newton SM, Wilkinson KA, Nicol MP, et al. Association between Gc genotype and susceptibility to TB is dependent on vitamin D status. Eur Respir J 2010; 35: 1106-1112.
24.Morrison NA, Qi JC, Tokita A, Kelly PJ, Crofts L, Nguyen TV, et al. Prediction of bone density from vitamin D receptor alleles. Nature 1994; 367: 284-287.
25.Chen C, Liu Q, Zhu L, Yang H, Lu W. Vitamin D receptor gene polymorphisms on the risk of tuberculosis, a meta-analysis of 29 case-control studies. Plos one 2013; 8: e83843.
26.Selvaraj P, Chandra G, Jawahar MS, Rani MV, Rajeshwari DN, Narayanan PR. Regulatory role of vitamin D receptor gene variants of Bsm I, Apa I, Taq I, and Fok I polymorphisms on macrophage phagocytosis and lymphoproliferative response to mycobacterium tuberculosis antigen in pulmonary tuberculosis. J Clin Immunol 2004; 24: 523-532.
27.Uitterlinden AG, Fang Y, Van Meurs JB, Pols HA, Van Leeuwen JP. Genetics and biology of vitamin D receptor polymorphisms. Gene 2004; 338: 143-56.
28.Arai H, Miyamoto K, Taketani Y, Yamamoto H, Iemori Y, Morita K, et al. A vitamin D receptor gene polymorphism in the translation initiation codon: effect on protein activity and relation to bone mineral density in Japanese women. J Bone Miner Res 1997; 12: 915-921.
29.Gao L, Tao Y, Zhang L, Jin Q. Vitamin D receptor genetic polymorphisms and tuberculosis: updated systematic review and meta-analysis. Int J Tuberc Lung Dis 2010; 14: 15-23.
30.Eales LJ, Nye KE, Parkin JM, Weber JN, Forster SM, Harris JR, et al. Association of different allelic forms of group specific component with susceptibility to and clinical manifestation of human immunodeficiency virusinfection. Lancet 1987; 1: 999-1002.
31.Alonso A, Montesino M, Iturralde MJ, Vallejo G, Sancho M, Tena G, et al. GC subtyping and HIV infection in a Spanish population: no evidence of an association between GC subtypes and AIDS. Hum Hered 1990; 40: 34-37.
32.Cleve H, Weidinger S, Gurtler LG, Deinhardt F. AIDS: no association with the genetic systems GC (D-binding protein), ORM (orosomucoid = alpha-1-acid glycoprotein), and A2HS (alpha-2-HS-glycoprotein). Infection 1988; 16: 31-35.
33.Pronk JC, Frants RR, Crusius B, et al. No predictive value of GC phenotypes for HIV infection and progression to AIDS. Hum Genet 1988; 80: 181-182.
34.Papiha SS, White I, Roberts DF. Some genetic implications of isoelectric focusing of human red cell phosphoglucomutase (PGM1) and serum protein group specific component (Gc): genetic diversity in the populations of Himachal Pradesh, India. Hum Genet 1983; 63: 67-72.
35.Spitsyn VA, Titenko NV. Subtypes of serum group specific component (Gc) in normal conditions and in pathology. Genetika 1990; 26: 749-759.
36.Wilkinson RJ, Lange C. Vitamin D and tuberculosis: new light on a potent biologic therapy? Am J Respir Crit Care Med 2009; 179: 740-742.
37.Selvaraj P, Kurian SM, Uma H, Reetha AM, Narayanan PR. Influence of non-MHC genes on lymphocyte response to Mycobacterium tuberculosis antigens & tuberculin reactive status in pulmonary tuberculosis. Indian J Med Res 2000; 112: 86-92.
38.Lewis SJ, Baker I, Davey Smith G. Meta-analysis of vitamin D receptor polymorphisms and pulmonary tuberculosis risk. Int J Tuberc Lung Dis 2005; 9: 1174-1177.
39.Søborg C, Andersen AB, Range N, Malenganisho W, Friis H, Magnussen P, et al. Influence of candidate susceptibility genes on tuberculosis in a high endemic region. Mol Immunol 2007; 44: 2213-2220.

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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