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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 楊偉勛(Wei-Shiung Yang) | |
dc.contributor.author | Hung-Wen Chen | en |
dc.contributor.author | 陳虹文 | zh_TW |
dc.date.accessioned | 2021-06-16T08:26:32Z | - |
dc.date.available | 2016-02-25 | |
dc.date.copyright | 2014-02-25 | |
dc.date.issued | 2014 | |
dc.date.submitted | 2014-01-20 | |
dc.identifier.citation | 1. World Health Organization,WHO, http://www.who.int/diabetes/en/
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/58703 | - |
dc.description.abstract | 第 1 型糖尿病起源於胰島素的β細胞被破壞,而導致胰島素的製造不足,或者甚至完全沒有製造;胰島素的β細胞被破壞,絕大部份是由於免疫系統所造成。由於第 1 型糖尿病通常發生於幼年或是青少年,發病後必須長期注射胰島素以維持正常的生活,如果能夠在發病之前預防或是延緩胰島素的β細胞被破壞,即可能可以預防第 1 型糖尿病的發生,以達到早期預防及治療的目的。
大部分第 1 型糖尿病之遺傳相關研究,多是以白人族群為主,根據其研究結果已很明確證明特定HLA基因型和第 1 型糖尿病有高度相關,尤其是HLA-DR及HLA-DQ為最重要的區域。但是HLA對偶基因型在不同族群中的分布頻率有相當大的差異性,例如,在白人族群中和第 1 型糖尿病呈現正相關的單套體,在日本族群中是顯示不存在或是非常罕見。 雖然,在臺灣已有一些相關的研究,但大多規模較小、樣本數小於100人,並且只進行少數的HLA基因座的分析。本研究為了更了解HLA基因與第 1 型糖尿病之間的相關性,採用病例對照的相關研究(104個病人與504個對照組),使用SBT定序方式全面性檢視第 1 型糖尿病患及對照組檢體之HLA之A、B、C、DQB1、DPB1及DRB1對偶基因型,利用PLINK工具組進行病例與對照組的比較,評估HLA基因型於兩組之間的關聯性及差異性,並以勝算比(odds ratio, OR)來表示基因型對於疾病的風險程度。 本研究結果顯示,臺灣族群中與第 1 型糖尿病相關之HLA易感受性對偶基因型,與白人族群及日本族群相吻合的有DQB1*02:01(OR=4.65)、DRB1*03:01(OR=4.59)、DRB1*04:05(OR=3.52)、DQB1*03:02(OR=2.26)、DQB1*04:01(OR=2.20);在日本族群中顯示相關的DRB1*09:01,在本研究中則亦有相關的趨勢。但本研究中並沒有觀察到白人族群的易感受性對偶基因型DRB1*04:01及日本族群的易感受性對偶基因型DQB1*03:03。而本研究中觀察到的易感受性對偶基因型 B*58:01(OR=2.88)、Cw*03:02(OR=2.84)及DPB1*04:01(OR=3.24),在白人族群及日本族群中則沒有顯示相關。 此外,臺灣族群中與第 1 型糖尿病相關之HLA保護性對偶基因型,與白人族群及日本族群相吻合的有DRB1*08:03(OR=0.10)、DQB1*03:01(OR=0.11)、DQB1*06:01(OR=0.08);本研究中並沒有發現在白人族群中,第 1 型糖尿病HLA保護性對偶基因型DRB1*04:03、DQB1*03:01及日本族群的DRB1*15:02、*15:01、*04:06、DQB1*06:02。而本研究中觀察到的保護性對偶基因中,DRB1*11:01(OR=0.17)、DRB1*12:02(OR=0.05)在白人族群及日本族群中亦未發現有相關。 從上述比較臺灣族群與其他族群的研究結果,所觀察到有些第1 型糖尿病之HLA易感受性基因型及保護性基因型在臺灣族群中並未發現相關,不一定表示該對偶基因型非致病因子,而只能表示此對偶基因型非臺灣族群最致病的重要代表,可能是這幾個對偶基因型的頻率在臺灣族群的分布頻率較低,也可能可以解釋為何第 1 型糖尿病的盛行率在臺灣仍較白人族群低。 | zh_TW |
dc.description.abstract | Type 1 diabetes (T1D) is cause by destruction of pancreatic beta cells, which subsequently results in reduced or no production of insulin. It is an autoimmune process. Patients with T1D usually have their first clinical manifestations in childhood or adolescence, and thereafter need life-long insulin injections to prevent life-threatening events. If the destruction of pancreatic beta cells can be prevented or delayed in early life, the individuals with T1D susceptibility might have delayed or no onset of the disease.
Up to now, most T1D genetic researches were performed in Caucasians; strong evidence showed the human leukocyte antigen (HLA) genes, especially the HLA-DR and HLA-DQ loci, played critical roles. However, the HLA region has been shown to be quite heterogeneous across populations. For example, a susceptibility haplotype in Caucasians was shown to be very rare in Japanese. Although there have been several genetic studies addressing the association between HLA genes and T1D in Taiwan, most of them suffered from drawbacks such as small sample size (mostly less than 100 people) and limited HLA locus coverage (usually focusing on DR and DQ loci). To accomplish a more comprehensive study, we increased our sample size (104 T1D patients and 504 controls) and covered 6 HLA loci (HLA-A, -C, -B, -DRB1, -DQB1 and -DPB1). We used genetic statistic software package PLINK to perform analysis, and calculated the odds ratio (OR) of individual HLA alleles for the risk of T1D. Our study replicated several previously reported association signals, and also identified some novel associated alleles. Regarding the susceptibility alleles, we replicated five DR and DQ alleles (DQB1*02:01 (OR=4.65), DRB1*03:01(OR=4.59), DRB1*04:05(OR=3.52), DQB1*03:02 (OR=2.26), DQB1*04:01(OR=2.20)) previously reported in Caucasians, Han Chinese and/or Japanese. We also observed a trend toward statistical significance of DRB1*09:01 (OR=1.76, Bonferroni corrected P value=5.1x10-2), a susceptibility allele previously reported in Japanese. However, we did not observe associations with DRB1*04:01 (previously reported in Caucasians) or DQB1*03:03 (previously reported in Japanese). On the other hand, we observed significant susceptibility of B*58:01(OR=2.88), Cw*03:02(OR=2.84) and DPB1*04:01(OR=3.24), which were novel findings from this study and had not been previously reported in Caucasians or Japanese. Regarding the protective alleles, we replicated three DR and DQ alleles (DRB1*08:03(OR=0.10), DQB1*03:01(OR=0.11), DQB1*06:01(OR=0.08)), previously reported in Caucasians, Han Chinese and/or Japanese. However, we did not observe associations with DRB1*04:03, DQB1*03:01 (previously reported in Caucasians) or DRB1*15:02, *15:01, *04:06, DQB1*06:02 (previously reported in Japanese). On the other hand, we observed significant protective of DRB1*11:01(OR=0.17), DRB1*12:02(OR=0.05), which were novel findings from this study and had not been previously reported in Caucasians or Japanese. Comparing our results in Taiwanese and others’ results in various other populations, we noticed that some of the previously reported associations were not replicated in our study. Such a situation does not necessarily exclude those alleles from T1D risk association. One possible explanation is that those alleles might have much lower allele frequencies in Taiwan, and therefore the statistical power was not good enough for our study to detect the association. Such kind of allele frequency discrepancy might also account for the T1D prevalence difference across populations. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T08:26:32Z (GMT). No. of bitstreams: 1 ntu-103-P00448013-1.pdf: 3789169 bytes, checksum: 5d24c9fc8d475d5b1bb49f122ad5e2cb (MD5) Previous issue date: 2014 | en |
dc.description.tableofcontents | 口試委員會審定書……………………………………………………………… I
中文摘要………………………………………………………………………… II- III 英文摘要………………………………………………………………………… IV- VI 目錄……………………………………………………………………………. VII -VIII 圖目錄…………………………………………………………………………… IX 表目錄…………………………………………………………………………… X 英文縮寫及中英文關鍵字……………………………………………………… XI-XII 第一章 導論…………………………………………………………………… 1 1.1糖尿病(Diabetes Mellitus,DM)……………………………………. 1 1.1.1 簡介………………………………………………………………. 1 1.1.2 臨床症狀及診斷分類……………………………………………. 2-4 1.1.3 糖尿病與基因的關係……………………………………………. 5-6 1.1.4 第 1 型糖尿病盛行率…………………………………………… 7 1.1.5 第 1 型糖尿病的診斷標準……………………………………… 8-9 1.1.6 第 1 型糖尿病致病機轉………………………………………… 10-11 1.2 人類白血球組織抗原(Human Leukocyte Antigen, HLA)………… 12 1.2.1主要組織相容性複合體(Major Histocompatibility Complex, MHC)…12-15 1.2.2 HLA分子結構…………………………………………………….. 16-18 1.2.3 HLA的功能……………………………………………………….. 19-20 1.2.4 HLA基因型分型………………………………………………….. 21-23 1.2.5 HLA基因型在族群中的分布…………………………………….. 24-25 1.3 第1型糖尿病與 HLA 之遺傳研究回顧……………………………. 26-27 第二章 實驗材料及方法…………….………………………………………… 28 2.1檢體收集………………………………………………………………... 28 2.2研究對象………………………………………………………………. 28 2.3實驗方法………………………………………………………………. 29-30 2.3.2 HLA基因分型………………………………………………….. 31-32 2.3.3 實驗器材與材料……………………………………………….. 33 2.4資料分析………………………………………………………………. 34-35 第三章 研究結果…………….………………………………………………… 36 3.1研究對象基本資料……………………………………………………. 36-37 3.2運用HLA關聯分析(Association Test)在無親屬關係之第 1型糖 尿病病例組和對照組………………………………… ……….. ……. 38-48 第四章 討論…………….…………………………………………………….... 49-54 參考文獻…………………………………………………………………….…55-64 附錄……………………………………………………………………………….. .65-79 | |
dc.language.iso | zh-TW | |
dc.title | 以全面性檢測HLA基因型進行第1型糖尿病之遺傳相關研究 | zh_TW |
dc.title | Comprehensive HLA genotyping to test for genetic association with type 1 diabetes mellitus | en |
dc.type | Thesis | |
dc.date.schoolyear | 102-1 | |
dc.description.degree | 碩士 | |
dc.contributor.coadvisor | 陳沛隆(Pei-Lung Chen) | |
dc.contributor.oralexamcommittee | 蔡文友 | |
dc.subject.keyword | 第1 型糖尿病,HLA,對偶基因型,直接定序法,勝算比,PLINK, | zh_TW |
dc.subject.keyword | Type 1 diabetes,HLA,allele,SBT,Odds Ratios,PLINK toolset, | en |
dc.relation.page | 79 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2014-01-21 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 分子醫學研究所 | zh_TW |
顯示於系所單位: | 分子醫學研究所 |
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