(3.227.0.150) 您好!臺灣時間:2021/05/06 12:57
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果

詳目顯示:::

我願授權國圖
: 
twitterline
研究生:林芯伃
研究生(外文):Shin-Yu Lin
論文名稱:建立DNA甲基化分析平台並應用於人類甲基化異常疾病與紅斑性狼瘡之臨床研究
論文名稱(外文):Establishment of analytic platform for DNA Methylation –Clinical Application in Human Methylation Disorders and Systemic Lupus Erythematosus
指導教授:何弘能何弘能引用關係
口試委員:郭保麟余家利蔡孟勳張舜治
口試日期:2013-05-20
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:臨床醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2013
畢業學年度:101
語文別:中文
論文頁數:121
中文關鍵詞:甲基化甲基化特異性聚合酶連鎖反應敏感性甲基化高解析熔解分析即時定量聚合酶連鎖反應併熔解分析專一性甲基化多重聚合酶連鎖反應專一性甲基化多重連接探針擴增技術小胖威利症天使症候群貝克威斯魏德曼症候群西弗羅素症候群紅斑性狼瘡
外文關鍵詞:MethylationMethylation-specific PCRMS-HRMQuantitative and qualitative real-time PCR with melting curve analysisMS multiplex PCRMS-MLPASystemic lupus erythematosusIL10IL1R2
相關次數:
  • 被引用被引用:0
  • 點閱點閱:477
  • 評分評分:系統版面圖檔系統版面圖檔系統版面圖檔系統版面圖檔系統版面圖檔
  • 下載下載:0
  • 收藏至我的研究室書目清單書目收藏:0
隨著人類基因圖譜的解密,科學家發現基因體調控序列的甲基化與基因的表現與否相關,DNA的甲基化調控著許多基因的活化與否,並控制許多基因的表現。DNA的甲基化,尤其是在基因啟動子區域中的 CpG島嶼上的胞嘧啶被DNA甲基轉移酶催化,形成5-甲基胞嘧啶,會阻礙轉錄因子與 DNA結合,進而導致基因靜默 (silencing)。當甲基化程度低下(hypomethylation)時,轉錄的工作就會被活化。目前已知基因體異常的甲基化可能會導致許多疾病的發生,例如癌症、免疫力缺乏以及自體免疫疾病等等。
我們的研究分為兩部分,第一部分是建立DNA甲基化分析平台,分析人類甲基化異常疾病(包含小胖威利症、天使症候群、貝克威斯魏德曼症候群以及西弗羅素症候群)的甲基化變異及基因劑量。我們建立了許多分析技術檢測DNA的甲基化,包括重亞硫酸鹽序列分析、甲基化特異性聚合酶連鎖反應、敏感性甲基化高解析熔解分析、即時定量聚合酶連鎖反應併熔解分析、專一性甲基化多重聚合酶連鎖反應以及專一性甲基化多重連接探針擴增技術。其中,由我們自行研發設計的「專一性甲基化多重聚合酶連鎖反應」及「即時定量聚合酶連鎖反應併熔解分析」可以在單一試管中同時分析DNA劑量及DNA甲基化程度,不但準確且可以提高檢測的效率、輸出率、方便性並避免檢體汙染。
研究的第二部分是利用全基因體甲基化晶片探討紅斑性狼瘡與DNA甲基化的關係。紅斑性狼瘡是一種複雜性的疾病,截至目前為止,真正的致病因子並不清楚,已知具有相當程度的遺傳傾向,但沒有單一基因突變可以解釋紅斑性狼瘡的發生。目前已經有許多研究證據認為DNA的甲基化低下在紅斑性狼瘡的發生扮演當重要的角色,因此,我們假設異常的DNA甲基化會活化免疫反應進而誘發紅斑性狼瘡的疾病活性。在我們第二部分的研究發現12名紅斑性狼瘡患者DNA甲基化的平均值確實比12名健康人的甲基化程度低(β值分別為0.048與0.054, p=0.0001),而且藉由生物知識資料庫軟分析發現到這些甲基化異常的基因可能牽涉到免疫細胞遷徙的生理網絡中。由此網絡,我們特別針對IL10與IL1R2基因進行分析,結果顯示這兩個基因在66名紅斑性狼瘡患者血中DNA甲基化的程度的確比102健康人顯著地低下(兩組IL10基因甲基化的平均值分別為0.272與0.428, p<0.0001,IL1R2則分別為0.043與0.103, p<0.0001),而且,愈嚴重的紅斑性狼瘡患者其IL10與IL1R2基因DNA甲基化低下的程度愈明顯,且比例愈高。透過線性迴歸分析,我們發現當個體具有IL10基因甲基化低下時,罹患紅斑性狼瘡的勝算比是22.061(95% 信賴區間為9.643-50.473),而具有IL1R2基因甲基化低下時,罹患紅斑性狼瘡的勝算比是10.533 (95% 信賴區間為4.960-22.365)。若是具有IL10或IL1R2基因一股甲基化低下,則罹病的勝算比為2.476 (95% 信賴區間為0.903-113.904),若同時兩個基因皆發生甲基化低下的現象,則罹病的勝算比為40.857(95% 信賴區間為14.655-113.904,p for trend <0.0001),換言之,我們的研究顯示當個體具有IL10與IL1R2基因DNA甲基化低下時,就較容易得到紅斑性狼瘡或者紅斑性狼瘡的疾病活性就愈強。此外,我們還發現到類風濕性關節炎患者體內IL10與IL1R2基因DNA甲基化也有低下的情形,但是IL1R2基因的變化又比IL10的變化更為顯著。藉由此研究,未來IL10與IL1R2基因甲基化低下將可能可以成為自體免疫疾病臨床的生物外遺傳指標。


Epigenetics is defined as the investigation of “heritable changes in gene expression that occur without a change in DNA sequence”, with the methylation of DNA and acetylation of histones being involved in such changes. Cytosine methylation of the regulatory sequences of DNA is an epigenetic mechanism that is associated with transcriptional inactivation of genes, while hypomethylation contributes to the activation of transcription. Recent epigenetic investigations have contributed to the pathogenesis of various disorders, including cancer, immunodeficiency and autoimmunity.
There are two parts of our research. The first part is to establish the analytic platforms for DNA methylation. We used human DNA methylation diseases such as Prader-Willi syndrome, Angelman syndrome, Beckwith Wiedemann syndrome and Silver Russell syndrome as our disease models to analyze the genetic dosage and DNA methylation pattern. We have set up severeal analytic technologies to examine the DNA methylation, including Methylation-specific PCR, Methylation-sensitive high resolution melting ananlysis, Quantitative and qualitative real-time PCR with melting curve analysis, Methylation-specific multiplex PCR and Methylation-specific multiplex ligation-dependent probe amplification. The noval methods, 「quantitative and qualitative real-time PCR with melting curve analysis」and 「methylation-specific multiplex PCR」 are developed by us. With these two methods, we can analyze both allelic copy numbers and DNA methylation patterns within one single tube, providing accurate, high-throughput, efficient results.
After establishing the analytic platforms for DNA methylation, we would like to apply the technologies to study complex human disease further. The second part of our research is to investigate epigetic changes over systemic lupus erythematosus(SLE) by whole genome methylation array. The etiology of systemic lupus erythematosus involves a complex interaction of genetic and environmental factors. Investigations have shown that environmentally driven epigenetic changes contribute to the etiology of SLE. Here, we hypothesized that aberrant DNA methylation may contribute to the activation of the immune machinery and trigger lupus disease activity. A whole genome methylation array was applied to investigate the DNA methylation changes between 12 pairs of active SLE patients and healthy controls. The results were further confirmed in 66 SLE patients and 102 healthy controls. The methylation statuses of the IL10 and IL1R2 genes were significantly reduced in the SLE patient samples relative to the healthy controls (age-adjusted odds ratios, 64.2 and 16.9, respectively, P<0.0001). There was a trend toward SLE patients having hypomethylated IL10 and IL1R2 genes accompanied by greater disease activity. We observed the methylation degree of IL10 and IL1R2 genes were reduced in the rheumatoid arthritis(RA) patients as well but the hypomethylation change was more significant in IL1R2 genes than in the IL10 genes in RA patients. This study demonstrated that DNA hypomethylation might be associated with SLE. Hypomethylated IL10 and IL1R2 genes may provide potential epigenetic markers as clinical predictors for autoimmune diseases.


口試委員會審定書…………………………………………………………… i
誌謝…………………………………………………………………………… ii
中文摘要……………………………………………………………………… iii~iv
英文摘要……………………………………………………………………… v~vi
博士論文內容
第一章 緒論
第一節 外遺傳調控與DNA甲基化………………………………… 1
第二節 DNA甲基化程度定性與定量
1. 重亞硫酸鹽分析……………………………………..……... 1~2
2. 非重亞硫酸鹽分析…………………………………..……... 2~3
第三節 人類甲基化異常疾病
1. 染色體15q11-13—小胖威利症候群與天使症候群.……... 3~4
2. 染色體11p15—貝克威斯魏德曼症候群與西弗羅素症….. 4~5
第四節 紅斑性狼瘡與DNA異常甲基化…………………..……….. 5~7
第二章 研究方法與材料
第一節 材料……………………………………………………...……. 8
第二節 DNA甲基化平台
1. DNA萃取………………………………………………......… 8
2. 重亞硫酸鹽處理……………………………………………... 9
3. 甲基化特異性聚合酶連鎖反應……………………………... 9
4. 專一性甲基化多重聚合酶連鎖反應…………………..…… 9~11
5. 專一性甲基化多重連接探針擴增技術…………………… 11~12
6. 敏感性甲基化高解析熔解分析…………………………… 12~13
7. 即時定量聚合酶連鎖反應併熔解分析…………………… 13~14
第三節 紅斑性狼瘡之甲基化研究
1. 全基因體甲基化基因晶片………………………………… 14
2. 生物知識資料庫軟體……………………………………… 15
3. 專一性甲基化單核苷酸引子延伸法……………………… 15~16
4. 重亞硫酸鹽基因定序法…………………………………… 16
5. 蛋白質定量…………………………………………….…… 16
6. 統計………………………………………………….……... 16~17
第三章 結果
第一節 建立DNA甲基化分析平台
1. 甲基化特異性聚合酶連鎖反應……………………….…… 18
2. 專一性甲基化多重聚合酶連鎖反應……………………… 18~19
3. 專一性甲基化多重連接探針擴增技術…………………… 19~20
4. 敏感性甲基化高解析熔解分析…………………………… 20~21
5. 即時定量聚合酶連鎖反應併熔解分析…………………… 22~23
第二節 紅斑性狼瘡之DNA甲基化分析研究
1. 全基因體甲基化基因晶片………………………………… 23
2. 生物知識資料庫軟體分析………………………………… 23
3. 以專一性甲基化單核苷酸引子延伸法進行甲基化定量... 23~25
4. 紅斑性狼瘡疾病感受性……………………………….…… 25
5. 蛋白質定量…………………………………………….…... 25~26
6. 基因甲基化程度與紅斑性狼瘡活性………………….…… 26
第四章 討論
第一節 建立DNA甲基化分析平台………………………….…... 27~29
第二節 紅斑性狼瘡之DNA甲基化分析研究……………….…... 29~35
第五章 展望………………………….……………………………………..... 36~43
第六章 論文英文簡述……………….…………………………………….... 44~58
第七章 參考文獻……………….………………………………………….... 59~69
第八章 附圖
圖1…………………………………………………………………………… 70
圖2…………………………………………………………………………… 71
圖3…………………………………………………………………………… 72
圖4…………………………………………………………………………… 73
圖5 ……………………………………………………………………………. 74
圖6…………………………………………………………………………… 75
圖7…………………………………………………………………………… 76
圖8…………………………………………………………………………… 77
圖9……………………………………………………………………………. 78
圖10…………………………………………………………………………… 79
圖11…………………………………………………………………………… 80
圖12…………………………………………………………………………… 81
圖13……………………………………………………………………………. 82
圖14…………………………………………………………………………… 83
圖15…………………………………………………………………………… 84
圖16…………………………………………………………………………… 85
圖17……………………………………………………………………………. 86
圖18…………………………………………………………………………… 87
圖19…………………………………………………………………………… 88
圖20……………………………………………………………………………. 89
圖21……………………………………………………………………………. 90
圖22……………………………………………………………………………. 91
圖23……………………………………………………………………………. 92
圖24……………………………………………………………………………. 93
圖25……………………………………………………………………………. 94
圖26……………………………………………………………………………. 95
圖27……………………………………………………………………………. 96
圖28……………………………………………………………………………. 97
圖29……………………………………………………………………………. 98
圖30……………………………………………………………………………. 99
第九章 附表
表一…...…………………………………………………………………… 100~101
表二…………………………………………………………………………102~103
表三…………………………………………………………………………104~111
表四…………………………………………………………………………….. 112
表五…………………………………………………………………………113~114
表六…………………………………………………………………………115~117
附錄
1. 碩博士班修業期間所發表之論文清冊……………………………118~121
2. 博士研究主題相關之已發表論文



1.Bird A. Perceptions of epigenetics. Nature 2007; 447: 396-8.
2.Robertson KD and Jones PA. DNA methylation: past, present and future directions. Carcinogenesis 2000; 21: 461-7.
3.Li E, Beard C and Jaenisch R. Role for DNA methylation in genomic imprinting. Nature 1993; 366: 362-5.
4.Gardiner-Garden M and Frommer M. CpG islands in vertebrate genomes. J Mol Biol 1987; 196: 261-82.
5.Ehrlich M, Gama-Sosa MA, Huang LH, Midgett RM, Kuo KC, McCune RA, et al. Amount and distribution of 5-methylcytosine in human DNA from different types of tissues of cells. Nucleic Acids Res 1982; 10: 2709-21.
6.Feinberg AP. Phenotypic plasticity and the epigenetics of human disease. Nature 2007; 447: 433-40.
7.Jones PA and Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet 2002; 3: 415-28.
8.Kubota T, Das S, Christian SL, Baylin SB, Herman JG and Ledbetter DH. Methylation-specific PCR simplifies imprinting analysis. Nat Genet 1997; 16: 16-7.
9.Cottrell SE, Distler J, Goodman NS, Mooney SH, Kluth A, Olek A, et al. A real-time PCR assay for DNA-methylation using methylation-specific blockers. Nucleic Acids Res 2004; 32: e10.
10.Couvert P, Poirier K, Carrie A, Chalas C, Jouannet P, Beldjord C, et al. DHPLC-based method for DNA methylation analysis of differential methylated regions from imprinted genes. Biotechniques 2003; 34: 356-62.
11.Deng D, Deng G, Smith MF, Zhou J, Xin H, Powell SM, et al. Simultaneous detection of CpG methylation and single nucleotide polymorphism by denaturing high performance liquid chromatography. Nucleic Acids Res 2002; 30: E13.
12.Baumer A, Wiedemann U, Hergersberg M and Schinzel A. A novel MSP/DHPLC method for the investigation of the methylation status of imprinted genes enables the molecular detection of low cell mosaicisms. Hum Mutat 2001; 17: 423-30.
13.Gonzalgo ML and Jones PA. Rapid quantitation of methylation differences at specific sites using methylation-sensitive single nucleotide primer extension (Ms-SNuPE). Nucleic Acids Res 1997; 25: 2529-31.
14.Ehrich M, Nelson MR, Stanssens P, Zabeau M, Liloglou T, Xinarianos G, et al. Quantitative high-throughput analysis of DNA methylation patterns by base-specific cleavage and mass spectrometry. Proc Natl Acad Sci U S A 2005; 102: 15785-90.
15.Dahl C and Guldberg P. A ligation assay for multiplex analysis of CpG methylation using bisulfite-treated DNA. Nucleic Acids Res 2007; 35: e144.
16.Schumacher A, Kapranov P, Kaminsky Z, Flanagan J, Assadzadeh A, Yau P, et al. Microarray-based DNA methylation profiling: technology and applications. Nucleic Acids Res 2006; 34: 528-42.
17.White HE, Hall VJ and Cross NC. Methylation-sensitive high-resolution melting-curve analysis of the SNRPN gene as a diagnostic screen for Prader-Willi and Angelman syndromes. Clin Chem 2007; 53: 1960-2.
18.Wojdacz TK and Dobrovic A. Methylation-sensitive high resolution melting (MS-HRM): a new approach for sensitive and high-throughput assessment of methylation. Nucleic Acids Res 2007; 35: e41.
19.Ehrich M, Zoll S, Sur S and van den Boom D. A new method for accurate assessment of DNA quality after bisulfite treatment. Nucleic Acids Res 2007; 35: e29.
20.Fraga MF and Esteller M. DNA methylation: a profile of methods and applications. Biotechniques 2002; 33: 632, 4, 6-49.
21.Grunau C, Clark SJ and Rosenthal A. Bisulfite genomic sequencing: systematic investigation of critical experimental parameters. Nucleic Acids Res 2001; 29: E65-5.
22.Callinan PA and Feinberg AP. The emerging science of epigenomics. Hum Mol Genet 2006; 15 Spec No 1: R95-101.
23.Boumil RM, Ogawa Y, Sun BK, Huynh KD and Lee JT. Differential methylation of Xite and CTCF sites in Tsix mirrors the pattern of X-inactivation choice in mice. Mol Cell Biol 2006; 26: 2109-17.
24.van Kamp H, Jansen R, Willemze R, Fibbe WE and Landegent JE. Studies on clonality by PCR analysis of the PGK-1 gene. Nucleic Acids Res 1991; 19: 2794.
25.Nygren AO, Ameziane N, Duarte HM, Vijzelaar RN, Waisfisz Q, Hess CJ, et al. Methylation-specific MLPA (MS-MLPA): simultaneous detection of CpG methylation and copy number changes of up to 40 sequences. Nucleic Acids Res 2005; 33: e128.
26.Dikow N, Nygren AO, Schouten JP, Hartmann C, Kramer N, Janssen B, et al. Quantification of the methylation status of the PWS/AS imprinted region: comparison of two approaches based on bisulfite sequencing and methylation-sensitive MLPA. Mol Cell Probes 2007; 21: 208-15.
27.Singer-Sam J, LeBon JM, Tanguay RL and Riggs AD. A quantitative HpaII-PCR assay to measure methylation of DNA from a small number of cells. Nucleic Acids Res 1990; 18: 687.
28.Gunay-Aygun M, Schwartz S, Heeger S, O''Riordan MA and Cassidy SB. The changing purpose of Prader-Willi syndrome clinical diagnostic criteria and proposed revised criteria. Pediatrics 2001; 108: E92.
29.Holm VA, Cassidy SB, Butler MG, Hanchett JM, Greenswag LR, Whitman BY, et al. Prader-Willi syndrome: consensus diagnostic criteria. Pediatrics 1993; 91: 398-402.
30.Williams CA, Beaudet AL, Clayton-Smith J, Knoll JH, Kyllerman M, Laan LA, et al. Angelman syndrome 2005: updated consensus for diagnostic criteria. Am J Med Genet A 2006; 140: 413-8.
31.Buiting K, Saitoh S, Gross S, Dittrich B, Schwartz S, Nicholls RD, et al. Inherited microdeletions in the Angelman and Prader-Willi syndromes define an imprinting centre on human chromosome 15. Nat Genet 1995; 9: 395-400.
32.Fridman C, Varela MC, Kok F, Setian N and Koiffmann CP. Prader-Willi syndrome: genetic tests and clinical findings. Genet Test 2000; 4: 387-92.
33.Glenn CC, Driscoll DJ, Yang TP and Nicholls RD. Genomic imprinting: potential function and mechanisms revealed by the Prader-Willi and Angelman syndromes. Mol Hum Reprod 1997; 3: 321-32.
34.Fang P, Lev-Lehman E, Tsai TF, Matsuura T, Benton CS, Sutcliffe JS, et al. The spectrum of mutations in UBE3A causing Angelman syndrome. Hum Mol Genet 1999; 8: 129-35.
35.Lossie AC, Whitney MM, Amidon D, Dong HJ, Chen P, Theriaque D, et al. Distinct phenotypes distinguish the molecular classes of Angelman syndrome. J Med Genet 2001; 38: 834-45.
36.Kubota T, Sutcliffe JS, Aradhya S, Gillessen-Kaesbach G, Christian SL, Horsthemke B, et al. Validation studies of SNRPN methylation as a diagnostic test for Prader-Willi syndrome. Am J Med Genet 1996; 66: 77-80.
37.Dittrich B, Buiting K, Korn B, Rickard S, Buxton J, Saitoh S, et al. Imprint switching on human chromosome 15 may involve alternative transcripts of the SNRPN gene. Nat Genet 1996; 14: 163-70.
38.Kosaki K, McGinniss MJ, Veraksa AN, McGinnis WJ and Jones KL. Prader-Willi and Angelman syndromes: diagnosis with a bisulfite-treated methylation-specific PCR method. Am J Med Genet 1997; 73: 308-13.
39.Velinov M, Gu H, Genovese M, Duncan C, Brown WT and Jenkins E. The feasibility of PCR-based diagnosis of Prader-Willi and Angelman syndromes using restriction analysis after bisulfite modification of genomic DNA. Mol Genet Metab 2000; 69: 81-3.
40.White HE, Durston VJ, Harvey JF and Cross NC. Quantitative analysis of SNRPN(correction of SRNPN) gene methylation by pyrosequencing as a diagnostic test for Prader-Willi syndrome and Angelman syndrome. Clin Chem 2006; 52: 1005-13.
41.Thorburn MJ, Wright ES, Miller CG and Smith-Read EH. Exomphalos-macroglossia-gigantism syndrome in Jamaican infants. Am J Dis Child 1970; 119: 316-21.
42.DeBaun MR, Niemitz EL, McNeil DE, Brandenburg SA, Lee MP and Feinberg AP. Epigenetic alterations of H19 and LIT1 distinguish patients with Beckwith-Wiedemann syndrome with cancer and birth defects. Am J Hum Genet 2002; 70: 604-11.
43.DeBaun MR and Tucker MA. Risk of cancer during the first four years of life in children from The Beckwith-Wiedemann Syndrome Registry. J Pediatr 1998; 132: 398-400.
44.Li M, Squire J, Shuman C, Fei YL, Atkin J, Pauli R, et al. Imprinting status of 11p15 genes in Beckwith-Wiedemann syndrome patients with CDKN1C mutations. Genomics 2001; 74: 370-6.
45.Cooper WN, Luharia A, Evans GA, Raza H, Haire AC, Grundy R, et al. Molecular subtypes and phenotypic expression of Beckwith-Wiedemann syndrome. Eur J Hum Genet 2005; 13: 1025-32.
46.Enklaar T, Zabel BU and Prawitt D. Beckwith-Wiedemann syndrome: multiple molecular mechanisms. Expert Rev Mol Med 2006; 8: 1-19.
47.Abu-Amero S, Monk D, Frost J, Preece M, Stanier P and Moore GE. The genetic aetiology of Silver-Russell syndrome. J Med Genet 2008; 45: 193-9.
48.Abu-Amero S, Wakeling EL, Preece M, Whittaker J, Stanier P and Moore GE. Epigenetic signatures of Silver-Russell syndrome. J Med Genet 2010; 47: 150-4.
49.Horike S, Ferreira JC, Meguro-Horike M, Choufani S, Smith AC, Shuman C, et al. Screening of DNA methylation at the H19 promoter or the distal region of its ICR1 ensures efficient detection of chromosome 11p15 epimutations in Russell-Silver syndrome. Am J Med Genet A 2009; 149A: 2415-23.
50.Kassi E and Moutsatsou P. Estrogen receptor signaling and its relationship to cytokines in systemic lupus erythematosus. J Biomed Biotechnol 2010: 317452.
51.Deng C, Lu Q, Zhang Z, Rao T, Attwood J, Yung R, et al. Hydralazine may induce autoimmunity by inhibiting extracellular signal-regulated kinase pathway signaling. Arthritis Rheum 2003; 48: 746-56.
52.Gorelik G, Fang JY, Wu A, Sawalha AH and Richardson B. Impaired T cell protein kinase C delta activation decreases ERK pathway signaling in idiopathic and hydralazine-induced lupus. J Immunol 2007; 179: 5553-63.
53.Sawalha AH, Jeffries M, Webb R, Lu Q, Gorelik G, Ray D, et al. Defective T-cell ERK signaling induces interferon-regulated gene expression and overexpression of methylation-sensitive genes similar to lupus patients. Genes Immun 2008; 9: 368-78.
54.Gateva V, Sandling JK, Hom G, Taylor KE, Chung SA, Sun X, et al. A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nat Genet 2009; 41: 1228-33.
55.Deapen D, Escalante A, Weinrib L, Horwitz D, Bachman B, Roy-Burman P, et al. A revised estimate of twin concordance in systemic lupus erythematosus. Arthritis Rheum 1992; 35: 311-8.
56.Richardson B, Scheinbart L, Strahler J, Gross L, Hanash S and Johnson M. Evidence for impaired T cell DNA methylation in systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum 1990; 33: 1665-73.
57.Ballestar E, Esteller M and Richardson BC. The epigenetic face of systemic lupus erythematosus. J Immunol 2006; 176: 7143-7.
58.Scheinbart LS, Johnson MA, Gross LA, Edelstein SR and Richardson BC. Procainamide inhibits DNA methyltransferase in a human T cell line. J Rheumatol 1991; 18: 530-4.
59.Oelke K, Lu Q, Richardson D, Wu A, Deng C, Hanash S, et al. Overexpression of CD70 and overstimulation of IgG synthesis by lupus T cells and T cells treated with DNA methylation inhibitors. Arthritis Rheum 2004; 50: 1850-60.
60.Cornacchia E, Golbus J, Maybaum J, Strahler J, Hanash S and Richardson B. Hydralazine and procainamide inhibit T cell DNA methylation and induce autoreactivity. J Immunol 1988; 140: 2197-200.
61.Herman JG, Graff JR, Myohanen S, Nelkin BD and Baylin SB. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci U S A 1996; 93: 9821-6.
62.Hung CC, Lin SY, Lin SP, Niu DM, Lee NC, Cheng WF, et al. Identification of CpG methylation of the SNRPN gene by methylation-specific multiplex PCR. Electrophoresis 2009; 30: 410-6.
63.Kantor B, Kaufman Y, Makedonski K, Razin A and Shemer R. Establishing the epigenetic status of the Prader-Willi/Angelman imprinting center in the gametes and embryo. Hum Mol Genet 2004; 13: 2767-79.
64.Hung CC, Lin SY, Lin SP, Chen CP, Chen LY, Lee CN, et al. Quantitative and qualitative analyses of the SNRPN gene using real-time PCR with melting curve analysis. J Mol Diagn; 13: 609-13.
65.Hung CC, Lin SY, Lee CN, Cheng HY, Lin CY, Chang CH, et al. Identification of fibrillin-1 gene mutations in Marfan syndrome by high-resolution melting analysis. Anal Biochem 2009; 389: 102-6.
66.Hung CC, Lee CN, Chang CH, Jong YJ, Chen CP, Hsieh WS, et al. Genotyping of the G1138A mutation of the FGFR3 gene in patients with achondroplasia using high-resolution melting analysis. Clin Biochem 2008; 41: 162-6.
67.Portela A and Esteller M. Epigenetic modifications and human disease. Nat Biotechnol 2010; 28: 1057-68.
68.Wang W, Law HY and Chong SS. Detection and discrimination between deletional and non-deletional Prader-Willi and Angelman syndromes by methylation-specific PCR and quantitative melting curve analysis. J Mol Diagn 2009; 11: 446-9.
69.Hung CC, Lin SY, Lin SP, Chen CP, Chen LY, Lee CN, et al. Quantitative and qualitative analyses of the SNRPN gene using real-time PCR with melting curve analysis. J Mol Diagn 2011; 13: 609-13.
70.Lourenco EV and La Cava A. Cytokines in systemic lupus erythematosus. Curr Mol Med 2009; 9: 242-54.
71.Linker-Israeli M, Deans RJ, Wallace DJ, Prehn J, Ozeri-Chen T and Klinenberg JR. Elevated levels of endogenous IL-6 in systemic lupus erythematosus. A putative role in pathogenesis. J Immunol 1991; 147: 117-23.
72.Viallard JF, Pellegrin JL, Ranchin V, Schaeverbeke T, Dehais J, Longy-Boursier M, et al. Th1 (IL-2, interferon-gamma (IFN-gamma)) and Th2 (IL-10, IL-4) cytokine production by peripheral blood mononuclear cells (PBMC) from patients with systemic lupus erythematosus (SLE). Clin Exp Immunol 1999; 115: 189-95.
73.Johanneson B, Lima G, von Salome J, Alarcon-Segovia D and Alarcon-Riquelme ME. A major susceptibility locus for systemic lupus erythemathosus maps to chromosome 1q31. American journal of human genetics 2002; 71: 1060-71.
74.Lopez P, Gutierrez C and Suarez A. IL-10 and TNFalpha genotypes in SLE. J Biomed Biotechnol 2010; 2010: 838390.
75.Jacobi AM, Odendahl M, Reiter K, Bruns A, Burmester GR, Radbruch A, et al. Correlation between circulating CD27high plasma cells and disease activity in patients with systemic lupus erythematosus. Arthritis Rheum 2003; 48: 1332-42.
76.Ito T, Hanabuchi S, Wang YH, Park WR, Arima K, Bover L, et al. Two functional subsets of FOXP3+ regulatory T cells in human thymus and periphery. Immunity 2008; 28: 870-80.
77.Liu Y, Zhu T, Cai G, Qin Y, Wang W, Tang G, et al. Elevated circulating CD4+ ICOS+ Foxp3+ T cells contribute to overproduction of IL-10 and are correlated with disease severity in patients with systemic lupus erythematosus. Lupus; 20: 620-7.
78.Llorente L, Zou W, Levy Y, Richaud-Patin Y, Wijdenes J, Alcocer-Varela J, et al. Role of interleukin 10 in the B lymphocyte hyperactivity and autoantibody production of human systemic lupus erythematosus. J Exp Med 1995; 181: 839-44.
79.Lauwerys BR, Garot N, Renauld JC and Houssiau FA. Interleukin-10 blockade corrects impaired in vitro cellular immune responses of systemic lupus erythematosus patients. Arthritis Rheum 2000; 43: 1976-81.
80.Llorente L, Richaud-Patin Y, Garcia-Padilla C, Claret E, Jakez-Ocampo J, Cardiel MH, et al. Clinical and biologic effects of anti-interleukin-10 monoclonal antibody administration in systemic lupus erythematosus. Arthritis Rheum 2000; 43: 1790-800.
81.Nath SK, Harley JB and Lee YH. Polymorphisms of complement receptor 1 and interleukin-10 genes and systemic lupus erythematosus: a meta-analysis. Human genetics 2005; 118: 225-34.
82.Brown MA. Genetics of ankylosing spondylitis. Curr Opin Rheumatol 2010; 22: 126-32.
83.Zheng Y, Humphry M, Maguire JJ, Bennett MR and Clarke MC. Intracellular interleukin-1 receptor 2 binding prevents cleavage and activity of interleukin-1alpha, controlling necrosis-induced sterile inflammation. Immunity; 38: 285-95.
84.Javierre BM, Fernandez AF, Richter J, Al-Shahrour F, Martin-Subero JI, Rodriguez-Ubreva J, et al. Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus. Genome Res 2010; 20: 170-9.
85.Mellor-Pita S, Citores MJ, Castejon R, Yebra-Bango M, Tutor-Ureta P, Rosado S, et al. Monocytes and T lymphocytes contribute to a predominance of interleukin 6 and interleukin 10 in systemic lupus erythematosus. Cytometry B Clin Cytom 2009; 76B: 261-70.
86.al-Janadi M, al-Dalaan A, al-Balla S, al-Humaidi M and Raziuddin S. Interleukin-10 (IL-10) secretion in systemic lupus erythematosus and rheumatoid arthritis: IL-10-dependent CD4+CD45RO+ T cell-B cell antibody synthesis. J Clin Immunol 1996; 16: 198-207.
87.Murakawa Y, Takada S, Ueda Y, Suzuki N, Hoshino T and Sakane T. Characterization of T lymphocyte subpopulations responsible for deficient interleukin 2 activity in patients with systemic lupus erythematosus. J Immunol 1985; 134: 187-95.
88.Chun HY, Chung JW, Kim HA, Yun JM, Jeon JY, Ye YM, et al. Cytokine IL-6 and IL-10 as biomarkers in systemic lupus erythematosus. J Clin Immunol 2007; 27: 461-6.
89.Llorente L, Richaud-Patin Y, Fior R, Alcocer-Varela J, Wijdenes J, Fourrier BM, et al. In vivo production of interleukin-10 by non-T cells in rheumatoid arthritis, Sjogren''s syndrome, and systemic lupus erythematosus. A potential mechanism of B lymphocyte hyperactivity and autoimmunity. Arthritis Rheum 1994; 37: 1647-55.
90.Zhao M, Tang J, Gao F, Wu X, Liang Y, Yin H, et al. Hypomethylation of IL10 and IL13 promoters in CD4+ T cells of patients with systemic lupus erythematosus. J Biomed Biotechnol 2010; 2010: 931018.
91.Merrill JT, Erkan D and Buyon JP. Challenges in bringing the bench to bedside in drug development for SLE. Nat Rev Drug Discov 2004; 3: 1036-46.
92.Lin SY, Lee CN, Hung CC, Tsai WY, Lin SP, Li NC, et al. Epigenetic profiling of the H19 differentially methylated region and comprehensive whole genome array-based analysis in Silver-Russell syndrome. Am J Med Genet A 2010; 152A: 2521-8.
93.Baylin SB, Herman JG, Graff JR, Vertino PM and Issa JP. Alterations in DNA methylation: a fundamental aspect of neoplasia. Adv Cancer Res 1998; 72: 141-96.
94.Chen RZ, Pettersson U, Beard C, Jackson-Grusby L and Jaenisch R. DNA hypomethylation leads to elevated mutation rates. Nature 1998; 395: 89-93.
95.Lin SY, Hsieh SC, Lin YC, Lee CN, Tsai MH, Lai LC, et al. A whole genome methylation analysis of systemic lupus erythematosus: hypomethylation of the IL10 and IL1R2 promoters is associated with disease activity. Genes Immun 2011; 13: 214-20.
96.Brown RS. Autoimmune thyroid disease: unlocking a complex puzzle. Curr Opin Pediatr 2009; 21: 523-8.
97.Jacobson EM and Tomer Y. The CD40, CTLA-4, thyroglobulin, TSH receptor, and PTPN22 gene quintet and its contribution to thyroid autoimmunity: back to the future. J Autoimmun 2007; 28: 85-98.
98.Jacobson EM, Huber A and Tomer Y. The HLA gene complex in thyroid autoimmunity: from epidemiology to etiology. J Autoimmun 2008; 30: 58-62.
99.Brix TH, Knudsen GP, Kristiansen M, Kyvik KO, Orstavik KH and Hegedus L. High frequency of skewed X-chromosome inactivation in females with autoimmune thyroid disease: a possible explanation for the female predisposition to thyroid autoimmunity. J Clin Endocrinol Metab 2005; 90: 5949-53.
100.Brynedal B, Duvefelt K, Jonasdottir G, Roos IM, Akesson E, Palmgren J, et al. HLA-A confers an HLA-DRB1 independent influence on the risk of multiple sclerosis. PLoS One 2007; 2: e664.
101.Lundmark F, Duvefelt K, Iacobaeus E, Kockum I, Wallstrom E, Khademi M, et al. Variation in interleukin 7 receptor alpha chain (IL7R) influences risk of multiple sclerosis. Nat Genet 2007; 39: 1108-13.
102.Zivadinov R, Uxa L, Bratina A, Bosco A, Srinivasaraghavan B, Minagar A, et al. HLA-DRB1*1501, -DQB1*0301, -DQB1*0302, -DQB1*0602, and -DQB1*0603 alleles are associated with more severe disease outcome on MRI in patients with multiple sclerosis. Int Rev Neurobiol 2007; 79: 521-35.
103.Hake SB, Xiao A and Allis CD. Linking the epigenetic ''language'' of covalent histone modifications to cancer. Br J Cancer 2007; 96 Suppl: R31-9.
104.Lu Q, Qiu X, Hu N, Wen H, Su Y and Richardson BC. Epigenetics, disease, and therapeutic interventions. Ageing Res Rev 2006; 5: 449-67.
105.Casaccia-Bonnefil P, Pandozy G and Mastronardi F. Evaluating epigenetic landmarks in the brain of multiple sclerosis patients: a contribution to the current debate on disease pathogenesis. Prog Neurobiol 2008; 86: 368-78.
106.Hansen T, Skytthe A, Stenager E, Petersen HC, Bronnum-Hansen H and Kyvik KO. Concordance for multiple sclerosis in Danish twins: an update of a nationwide study. Mult Scler 2005; 11: 504-10.
107.Poser CM. The multiple sclerosis trait and the development of multiple sclerosis: genetic vulnerability and environmental effect. Clin Neurol Neurosurg 2006; 108: 227-33.
108.Szyf M. DNA methylation properties: consequences for pharmacology. Trends Pharmacol Sci 1994; 15: 233-8.
109.Tomassini V and Pozzilli C. Sex hormones: a role in the control of multiple sclerosis? Expert Opin Pharmacother 2006; 7: 857-68.
110.Vukusic S and Confavreux C. Pregnancy and multiple sclerosis: the children of PRIMS. Clin Neurol Neurosurg 2006; 108: 266-70.
111.Kaminsky Z, Wang SC and Petronis A. Complex disease, gender and epigenetics. Ann Med 2006; 38: 530-44.
112.Liggett T, Melnikov A, Tilwalli S, Yi Q, Chen H, Replogle C, et al. Methylation patterns of cell-free plasma DNA in relapsing-remitting multiple sclerosis. J Neurol Sci 2010; 290: 16-21.
113.Schwab J and Illges H. Silencing of CD21 expression in synovial lymphocytes is independent of methylation of the CD21 promoter CpG island. Rheumatol Int 2001; 20: 133-7.
114.Karouzakis E, Gay RE, Michel BA, Gay S and Neidhart M. DNA hypomethylation in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum 2009; 60: 3613-22.
115.Schauenstein K, Csordas A, Kromer G, Dietrich H and Wick G. In-vivo treatment with 5-azacytidine causes degeneration of central lymphatic organs and induces autoimmune disease in the chicken. Int J Exp Pathol 1991; 72: 311-8.
116.Karouzakis E, Gay RE, Gay S and Neidhart M. Epigenetic control in rheumatoid arthritis synovial fibroblasts. Nat Rev Rheumatol 2009; 5: 266-72.
117.Dawson AJ, Chernos J, McGowan-Jordan J, Lavoie J, Shetty S, Steinraths M, et al. CCMG guidelines: prenatal and postnatal diagnostic testing for uniparental disomy. Clin Genet 2010; 79: 118-24.
118.Weksberg R, Smith AC, Squire J and Sadowski P. Beckwith-Wiedemann syndrome demonstrates a role for epigenetic control of normal development. Hum Mol Genet 2003; 12 Spec No 1: R61-8.
119.Baumer A. Analysis of the methylation status of imprinted genes based on methylation-specific polymerase chain reaction combined with denaturing high-performance liquid chromatography. Methods 2002; 27: 139-43.
120.Procter M, Chou LS, Tang W, Jama M and Mao R. Molecular diagnosis of Prader-Willi and Angelman syndromes by methylation-specific melting analysis and methylation-specific multiplex ligation-dependent probe amplification. Clin Chem 2006; 52: 1276-83.
121.Sawalha AH, Webb R, Han S, Kelly JA, Kaufman KM, Kimberly RP, et al. Common variants within MECP2 confer risk of systemic lupus erythematosus. PLoS ONE 2008; 3: e1727.


QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top
無相關期刊
 
系統版面圖檔 系統版面圖檔