Role of Genetic Polymorphisms in Predicting Delayed Cerebral Ischemia and Radiographic Vasospasm After Aneurysmal Subarachnoid Hemorrhage: A Meta-Analysis

Abstract

Objective: The pathophysiology on cerebral vasospasm and delayed cerebral ischemia (DCI) remains poorly understood. Much research has been dedicated to finding genetic loci associated with vasospasm and ischemia. We present a systematic review and meta-analysis to identify genetic polymorphisms associated with delayed ischemic neurologic deficit (DIND), radiographic infarction attributed to ischemia, and radiographic vasospasm.

Methods: PubMed, the Cochrane Library, and Excerpta Medica dataBASE (EMBASE) databases were used to identify relevant studies published up to March 2015 containing the subject terms cerebral or intracranial vasospasm and DCI in combination with genetics, gene, polymorphism or marker. Meta-analyses were performed using a random-effects model to calculate summary odds ratio (ORs) and 95% confidence intervals for each respective gene.

Results: Of 269 articles initially identified, 20 studies with 1670 patients were included in our comprehensive review, including 27 polymorphisms in 11 genes. The following 6 polymorphisms in 3 genes were selected for subsequent meta-analyses: apolipoprotein E (ApoE2, E4); endothelial nitric oxide (eNOS T786C, VNTR intron 4 a/b, G894T); and haptoglobin (Hp) 1/2 phenotypes. The eNOS VNTR a allele was associated with DIND (a vs. b allele: OR 1.92 [1.31-2.81], padj = 0.008). The Hp 2-2 allele was associated with radiographic vasospasm (2-2 vs. 2-1 and 1-1: OR 3.86 [1.86-8.03], padj = 0.003) but did not reach significance for DIND.

Conclusions: This is the first systemic review and meta-analysis to study and evaluate the associations between genetic polymorphism with DCI and radiographic vasospasm independently. In our study, eNOS VNTR and Hp polymorphisms appear to have the strongest associations with DIND and radiographic vasospasm, respectively.

Keywords: Delayed cerebral ischemia; Delayed ischemic neurologic deficit; Polymorphisms; Subarachnoid hemorrhage; Vasospasm.