OBJECTIVE Endothelin-1, a potent vasoconstrictor, and its receptors may be involved in the pathogenesis of aneurysmal subarachnoid hemorrhage (aSAH), clinical vasospasm, delayed cerebral ischemia (DCI), and functional outcome following aSAH. In the present study, common endothelin single nucleotide polymorphisms (SNPs) and their relation to aSAH were evaluated. METHODS Blood samples from all patients enrolled in the Cerebral Aneurysm Renin Angiotensin System (CARAS) study were used for genetic evaluation. The CARAS study prospectively enrolled patients with aSAH at 2 academic institutions in the US from 2012 to 2015. Common endothelin SNPs were detected using 5' exonnuclease (TaqMan) genotyping assays. Analysis of associations between endothelin SNPs and aSAH and its clinical sequelae was performed. RESULTS Samples from 149 patients with aSAH and 50 controls were available for analysis. In multivariate logistic regression analysis, the TG (odds ratio [OR] 2.102, 95% confidence interval [CI] 1.048-4.218, p = 0.036) and TT genotypes (OR 7.884, 95% CI 1.003-61.995, p = 0.05) of the endothelin-1 T/G SNP (rs1800541) were significantly associated with aSAH. There was a dominant effect of the G allele (CG/GG genotypes; OR 4.617, 95% CI 1.311-16.262, p = 0.017) of the endothelin receptor A G/C SNP (rs5335) on clinical vasospasm. Endothelin SNPs were not associated with DCI or functional outcome. CONCLUSIONS Common endothelin SNPs were found to be associated with presentation with aSAH and clinical vasospasm. Further studies are required to elucidate the relevant pathophysiology and its potential implications in the treatment of patients with aSAH.
Keywords: CARAS = Cerebral Aneurysm Renin Angiotensin System; CI = confidence interval; CONSCIOUS = Clazosentan to Overcome Neurological Ischemia and Infarct Occurring after Subarachnoid Hemorrhage; CTA = CT angiography; DCI = delayed cerebral ischemia; DSA = digital subtraction angiography; END1 = endothelin-1; ENDRA = endothelin receptor A; ENDRB = endothelin receptor B; ICU = intensive care unit; NO = nitric oxide; OR = odds ratio; SNP = single nucleotide polymorphism; TCD = transcranial Doppler ultrasonography; aSAH = aneurysmal subarachnoid hemorrhage; aneurysm; cerebral; delayed cerebral ischemia; endothelin; intracranial; mRS = modified Rankin scale; polymorphism; rupture; subarachnoid hemorrhage; vascular disorders; vasospasm.