Varinder S Alg1, Xiayi Ke2, Joan Grieve1, Stephen Bonner3, Daniel C Walsh4, Diederik Bulters5, Neil Kitchen1, Henry Houlden1, David J Werring1. 1. a Stroke Research Centre, Department of Brain Repair and Rehabilitation , Institute of Neurology, National Hospital for Neurology and Neurosurgery , London , UK. 2. b Institute of Child Health, Genetics & Genomic Medicine Programme , Institute of Child Health, Faculty of Pop Health Sciences, UCL , London , UK. 3. c Department of Neuroanaesthesia , James Cook University Hospital, Durham University , London , UK. 4. d Department of Neurosurgery, Neurovascular Surgery , Kings College Hospital , London , UK. 5. e Department of Neurovascular Surgery , University Hospital Southampton , Southampton , UK.
Abstract
INTRODUCTION: 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. MATERIALS AND METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.
INTRODUCTION: 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. MATERIALS AND METHODS: 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. RESULTS: 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). CONCLUSIONS: Our study demonstrated an association between the functional MMP-2rs243865 variant and IAs. Our findings suggest a genetic role for altered extracellular matrix integrity in the pathogenesis of IA development and rupture.
Authors: Brian Fiani; James B Fowler; Ryan Arthur Figueras; Keon Hessamian; Nathan Mercado; Olivia Vukcevich; Manpreet Kaur Singh Journal: Surg Neurol Int Date: 2021-04-26
Authors: Manuel Navarro-Oviedo; Roberto Muñoz-Arrondo; Beatriz Zandio; Juan Marta-Enguita; Anna Bonaterra-Pastra; Jose Antonio Rodríguez; Carmen Roncal; Jose A Páramo; Estefania Toledo; Joan Montaner; Mar Hernández-Guillamon; Josune Orbe Journal: Sci Rep Date: 2020-06-25 Impact factor: 4.996