Alg Varinder S, Ke Xiayi, Grieve Joan, Bonner Stephen, Walsh Daniel C, Bulters Diederik, Kitchen Neil, Houlden Henry, Werring David J
a Stroke Research Centre, Department of Brain Repair and Rehabilitation , Institute of Neurology, National Hospital for Neurology and Neurosurgery , London , UK.
b Institute of Child Health, Genetics & Genomic Medicine Programme , Institute of Child Health, Faculty of Pop Health Sciences, UCL , London , UK.
Br J Neurosurg. 2018 Jun;32(3):255-259. doi: 10.1080/02688697.2018.1427213. Epub 2018 Jan 15.
Abnormalities in Matrix Metalloproteinase (MMP) genes, which are important in extracellular matrix (ECM) maintenance and therefore arterial wall integrity are a plausible underlying mechanism of intracranial aneurysm (IA) formation, growth and subsequent rupture. We investigated whether the rs243865 C > T SNP (single nucleotide polymorphism) within the MMP-2 gene (which influences gene transcription) is associated with IA compared to matched controls.
We conducted a case-control genetic association study, adjusted for known IA risk factors (smoking and hypertension), in a UK Caucasian population of 1409 patients with intracranial aneurysms (IA), and 1290 matched controls, to determine the association of the rs243865 C > T functional MMP-2 gene SNP with IA (overall, and classified as ruptured and unruptured). We also undertook a meta-analysis of two previous studies examining this SNP.
The rs243865 T allele was associated with IA presence in univariate (OR 1.18 [95% CI 1.04-1.33], p = .01) and in multi-variable analyses adjusted for smoking and hypertension status (OR 1.16 [95% CI 1.01-1.35], p = .042). Subgroup analysis demonstrated an association of the rs243865 SNP with ruptured IA (OR 1.18 [95% CI 1.03-1.34] p = .017), but, not unruptured IA (OR 1.17 [95% CI 0.97-1.42], p = .11).
Our study demonstrated an association between the functional MMP-2 rs243865 variant and IAs. Our findings suggest a genetic role for altered extracellular matrix integrity in the pathogenesis of IA development and rupture.
基质金属蛋白酶（MMP）基因异常在细胞外基质（ECM）维持以及动脉壁完整性方面具有重要作用，这可能是颅内动脉瘤（IA）形成、生长及后续破裂的潜在机制。我们研究了MMP - 2基因内的rs243865 C>T单核苷酸多态性（SNP）（影响基因转录）与IA相比匹配对照之间的相关性。
我们在英国白种人群中进行了一项病例对照基因关联研究，对已知的IA风险因素（吸烟和高血压）进行了校正，研究对象包括1409例颅内动脉瘤（IA）患者和1290例匹配对照，以确定功能性MMP - 2基因SNP rs243865与IA（总体，以及分为破裂和未破裂）之间的关联。我们还对之前两项研究该SNP的研究进行了荟萃分析。
rs243865 T等位基因在单变量分析中与IA存在相关（比值比1.18 [95%可信区间1.04 - 1.33]，p = 0.01），在根据吸烟和高血压状态校正的多变量分析中也相关（比值比1.16 [95%可信区间1.01 - 1.35]，p = 0.042）。亚组分析显示rs243865 SNP与破裂IA相关（比值比1.18 [95%可信区间1.03 - 1.34]，p = 0.017），但与未破裂IA无关（比值比1.17 [95%可信区间0.97 - 1.42]，p = 0.11）。
我们的研究表明功能性MMP - 2 rs243865变异与IA之间存在关联。我们的研究结果提示细胞外基质完整性改变在IA发生发展和破裂的发病机制中具有遗传作用。
