硬腦膜動靜脈瘻管之基因多型性研究

Gene Polymorphism in Dural Arteriovenous Fistula

崔源生(Yuang-Seng Tsuei)

指導教授 ： 楊順發

中山醫學大學/醫學院/醫學研究所/博士(2018年)

摘要

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。

關鍵字

硬腦膜瘻管 ； 基質金屬蛋白酶單核苷酸多型性 ； 靜脈竇血栓 ； 靜脈高壓

並列摘要

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.

並列關鍵字

dural arteriovenous fistula ； matrix metalloproteinase ； single nucleotide polymorphism ； sinus thrombosis ； venous hypertension

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