臺灣博碩士論文加值系統

硬腦膜動靜脈瘻管(Dural Arteiovenous Fistula, DAVF)乃一較少見但重要之成人腦血管疾病，其病理病因學與分子生物學的研究相對付之闕如，本研究計畫主要分析相關生成刺激因子的基因多型性在硬腦膜動靜脈瘻管生成中或表現上所扮演的角色。本實驗收集72名罹患硬腦膜動靜脈瘻管受試者血液檢體，利用即時聚合酶連鎖反應(real-time Polymerase chain reaction, real-time PCR)方法，進行7種血管生成相關因子的單核苷酸多型性 (single-nucleotide polymorphism, SNP) 分析，包括有MMP-2 -1306 (rs243865)； MMP-9 (rs17576)；MMP-9 (rs9509)； TIMP-1 (rs4898)； TIMP-2 (rs2277698)； VEGFA (rs2010963)；VEGFA (rs3025039)。受試者的臨床與影像資料，則根據瘻管位置，瘻管病灶數，顱內腦靜脈反流分級(Borden I與Borden II / III)和靜脈竇血栓形成有無，進行四類次分組統計。本研究發現硬腦膜動靜脈瘻管受試者中，基質金屬蛋白酶(Matrix metalloproteinase, MMP)中的MMP-2-1306C/T (rs243865)多型性等位基因的個體更容易有併發靜脈竇血栓之情形，優勢比[Odds ratio, OD]，6.2； 95％信賴區間[Confidence interval, CI]，1.7至22.9；p值為0.006。也同時發現到硬腦膜動靜脈瘻管受試者中組織基質金屬蛋白酶抑制物-2，Tissue inhibitor of metalloproteinase, TIMP-2 (rs2277698)多型性等位基因的個體可能易有併發靜脈竇血栓之情形，優勢比[OD]，3.0；95％信賴區間[CI]，1.1至8.2；p值為0.026。本研究發現硬腦膜動靜脈瘻管受試者中，基質金屬蛋白酶-2， MMP-2-1306C/T (rs243865)多型性等位基因的個體，與容易有併發靜脈竇血栓有關，可用於做為臨床預期判斷，而MMP-9、TIMP-1、 TIMP-2與VEGFA等相關之單核苷酸多型性，則與硬腦膜動靜脈瘻管之表現無關。

Dural arteriovenous fistula (DAVF) is a rare but important cerebrovascular disorder in adults. Little is known about the molecular genetic pathogenesis underlying the development of DAVF. The present study was conducted to investigate the associations of gene polymorphisms and DAVF. Using real-time polymerase chain reaction (real-time PCR) genotyping, 7 single-nucleotide polymorphisms (SNPs) of angiogenesis-related genes, including MMP-2 -1306 (rs243865); MMP-9 (rs17576); MMP-9 (rs9509); TIMP-1 (rs4898); TIMP-2 (rs2277698); VEGFA (rs2010963); VEGFA (rs3025039) were analyzed in 72 DAVF patients. Pertinent clinical and imaging data were sub-grouped based on location (cavernous sinus versus non-cavernous sinus), lesions (single versus multiple), cerebral venous reflux (CVR) grading (Borden I versus Borden II/III), and sinus thrombosis (with versus without). We found that individuals carrying the polymorphic allele of matrix metalloproteinase (MMP)-2-1306 C/T (rs243865) were more susceptible to DAVF patients with sinus thrombosis (odds ratio [OR], 6.2; 95% confidence interval [CI], 1.7 to 22.9; p value=0.006). There was a weak difference in associations of TIMP-2 (rs2277698) gene polymorphism and DAVF patients sub-grouped by CVR grading (OR, 3.0; 95% CI, 1.1 to 8.2, p value=0.026). These results indicate that MMP-2-1306 C/T, but not MMP-9, TIMP-1, TIMP-2, and VEGFA SNPs variants, is a risk factor for the development of sinus thrombosis in DAVF.

目錄
縮寫檢索表............................................IV
摘要..................................................V
Abstract ...........................................VII

第一章 緒論 ......................................................1
一、硬腦膜動靜脈瘻管(Dural Arteriovenous Fistula).......1
1.1. 硬腦膜動靜脈瘻管之病理組織學定義....................1
1.2. 硬腦膜動靜脈瘻管之流行病學.........................2
1.3. 硬腦膜動靜脈瘻管生成之致病機轉......................2
1.4. 硬腦膜動靜脈瘻管之臨床臨床表徵......................2
1.5. 硬腦膜動靜脈瘻管之診斷.............................3
1.6. 硬腦膜動靜脈瘻管之分類.............................4
1.7. 硬腦膜動靜脈瘻管之治療.............................5
二、硬腦膜動靜脈瘻管分子生物學研究之文獻回顧..............6
2.1. 以硬腦膜動靜脈瘻管為關鍵字搜尋......................6
2.2. 以硬腦動靜脈畸型為關鍵字搜尋........................6
2.3. 基因多型性的研究選擇...............................7
三、血管新生調節因子....................................8
3.1. 基質金屬蛋白酶-2, MMP-2............................8
3.2. 基質金屬蛋白酶-9, MMP-9............................9
3.3. 組織基質金屬蛋白酶抑制物, TIMP......................9
3.4. 血管內皮生長因子, VEGF-A..........................10

第二章 實驗動機........................................11

第二章 實驗方法 .......................................12
一、實驗材料與方法......................................12
1.1. 實驗檢體及資料來源.................................12
1.2. 檢體採集與分離.....................................12
二、基因多型性的選擇....................................12
三、DNA之萃取..........................................13
四、即時定量聚合酶連鎖反應..............................14
五、統計分析...........................................15

第四章 結果 ...........................................16
一、臨床與影像學資料....................................16
二、硬腦膜動靜脈瘻管患者的基因多型性分布頻率..............16
三、基因多型性分布與靜脈竇血栓之關聯性...................17
四、基因多型性分布與顱內靜脈反流分類之關聯性..............18
五、基因多型性分布與瘻管發生部位之關聯性..................19
六、基因多型性分布與瘻管病灶數之關性.....................19

第五章 討論 ...........................................20

第六章 結論與建議.......................................25

參考文獻 ..............................................26
圖表與結果說明 ........................................36
表一 受試者之基本特性與次分類分布表......................37
表二 硬腦膜動靜脈瘻管受試者的基因多型性分布頻率...........38
表三 基因多型性分布與靜脈竇血栓之關聯性之關聯性...........39
表四 基因多型性分布與顱內反流分類之關聯性................41
表五 基因多型性分布與瘻管發生部位之關聯性................43
表六 基因多型性分布與瘻管病灶數之關聯性之關聯性...........45
附錄 .................................................47
已發表論文............................................51

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