中文摘要
反覆發作性關節炎是一個自體發炎反應的罕見疾病，其症狀為關節及週邊組織發炎呈現反覆發作的情形;我們研究的目的在於探討腫瘤壞死因子(TNF-α, TNFRSF1A and TNFRSF1B),間白素-1 (Interleukin-1β)等這些促進發炎的細胞素共10個單一核苷酸基因多型性(SNP)其基因多型性與反覆發作性關節炎的相關性。
本實驗從高雄榮民總醫院取樣56位反覆發作性關節炎病患與100位與此疾病無關的正常人，利用探針引子對156位實驗對象進行腫瘤壞死因子-α(TNF-α)，腫瘤壞死因子接受器(TNFRS)及間白素-1β(IL-1β)進行PCR反應及偵測其螢光反應的變化，並進行基因多型性分型和統計分析;結果顯示除腫瘤壞死因子接受器-A+36AG基因型(TNFRSF1A+36AG genotype)的基因多型性與反覆發作性關節炎的感受性有顯著意義 (OR=4.8，95% CI=1.8-13.0，p=0.002)，腫瘤壞死因子接受器-A+36G對偶基因型也有顯著意義(OR=3.94，95﹪CI=1.59-9.79，p=0.003) ；此外腫瘤壞死因子接受器-B半套體(TNFRSF1B haplotype)+676/+1663T/A也具相關性(OR=2.12，CI=1.2-3.8，p=0.010)。但在腫瘤壞死因子α以及間白素-1β的基因型、對偶基因型以及半套體分析都沒有關聯性。
結論: 腫瘤壞死因子接受器(TNFRSF1A，TNFRSF1B)基因多型性與反覆發作性關節炎病患發炎反應感受性具相關性。

ABSTRACT
Background: Palindromic rheumatism (PR) is the rare disease that generally occurs with multiple recurring attacks of painful inflammation affecting joints and adjacent tissues. The thesis attempts to characterize the association in 10 instances of the single nucleotide polymorphisms (SNPs) of tumor necrosis factor genes (TNF-α, TNFRSF1A and TNFRSF1B), Interleukin-1β genes and Palindromic rheumatism (PR). Methods: The genetic polymorphisms of TNF-α, TNFRΙ, TNFRΠ and IL-1β genes cluster were investigated among 56 PR patients identified from the Kaohsiung Veterans General Hospital (VGHKS, Kaohsiung, Taiwan) and compared with one hundred healthy subjects. The genotypes for ten SNPs in the TNF-α, TNFRSF1A, TNFRSF1B and IL-1β genes among these 156 individuals were examined.
Results: Experiments indicate significant count of the TNFRSF1A+36 AG genotype in PR patients (OR=4.8, 95%CI=1.8-13.0, p=0.002) and TNFRSF1A+36G allele (OR=3.94, 95%CI=1.59-9.79, p=0.003).The results also have remarkable correlation with TNFRSF1B haplotype +676/+1663 T/A (OR=2.12, CI=1.2-3.8, p=0.010). However, on significant differences were found for all the TNF-αand IL-1βpolymorphisms.
Conclusions: Genetic polymorphisms in TNF-α receptors are associated with susceptibility and severity of the inflammatory response in the PR patients.

目錄 頁次
表目錄 5
圖目錄 6
縮寫 7
壹.前言 8
一.反覆發作性關節炎 8
二.風濕性關節炎 11
三.家族性地中海熱 13
四.反覆發作性關節炎與細胞素的關係 15
4.1腫瘤壞死因子α 16
4.2腫瘤壞死因子接受器 18
4.3間白素-1β 19
貳.研究目的 21
參.實驗材料與方法 22
一.實驗器材與儀器 22
二.檢體樣本 22
2.1病患與正常人檢體來源 22
2.2檢體採集及分析 23
2.3 血清風濕性因子， 抗核抗體，anti-CCP IgG ，紅血球沉降速率的分析 23
2.4 DNA之萃取 24
三.實驗方法 25
3.1引子(primer) 25
3.2PCR反應 25
3.3PCR反應物的分析(SNP Genotyping) 26
四.統計方法Statistical analysis 26
肆.結果 27
伍.討論 29
表目錄 頁次
表一:病患組與對照組年齡性別分佈情形 34
表二:反覆發作性關節炎各項檢查結果 35
表三:實驗中使用的SNP 相關資料 36
表四:反覆發作性關節炎與控制組TNF-α-308/-238/+488基因型
，對偶基因型頻率之比較 37
表五:反覆發作性關節炎與控制組TNFRSF1A-609/+36基因型，
對偶基因型頻率比較 38
表六:反覆發作性關節炎與控制組TNFRSF1B+676/+1663基因型，
對偶基因型頻率之比較 39
表七:反覆發作性關節炎與控制組IL-1β-511/-31/+3954基因型
，對偶基因型頻率之比較 40
表八:反覆發作性關節炎與控制組TNF-α/TNFRS/IL-1β
基因半套體頻率之比較 41
參考資料 42

圖目錄 頁次
圖一:發炎反應細胞間的調控 51
圖二:全身性發炎反應 52
圖三:HLA基因圖 53
圖四: 圖四.TNF-α SNP的相關位置 54
圖五: TNF異常造成各項慢性發炎疾病A 55
圖六: TNFα與TNFR1結合之訊號傳遞 56
圖七: TNFα與TNFR2結合後之訊號傳遞 57
圖八: BI Prism7000螢光圖 58
圖九: Allele discrimination 軟體分析結果 59
圖十: ABI Prism 7000 Real time PCR螢光擴增曲線圖 60

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