Cerebral Vasospasm after Sub-arachnoid Hemorrhage as a Clinical Predictor and Phenotype for Genetic Association Study

Abstract

A typology of cerebral vasospasm has been proposed based on distinct clinical manifestations: delayed cerebral ischemia, symptomatic 'vasospasm', angiographic vasospasm, and transcranial Doppler vasospasm. We examined each distinct clinical manifestation in a nonparametric genetic association study. The purpose of this study was to examine and compare each four distinct acute clinical manifestations and test its perspectives in genetic association studies. Two hundred forty-five Caucasian patients with sub-arachnoid hemorrhage were evaluated for these four distinct clinical manifestations along with 906 600 single-nucleotide polymorphisms across the human genome. The four clinical manifestations were significantly associated with each other as P-values ranged from 3·31 × 10(-4) to 8·10 × 10(-15) . Transcranial Doppler vasospasm showed significant genetic association with single nucleotide polymorphism (SNP) (rs999662, P = 3·39 × 10(-8) ). Statistical P-value of rs999662 in association with delayed cerebral ischemia, symptomatic 'vasospasm', and angiographic vasospasm was 0·0017, 0·0017, and 0·19, respectively. Despite different criteria for each of the four clinical manifestations, they are significantly associated with each other. Our results suggest transcranial Doppler vasospasm may be an appropriate intermediate but still clinically relevant phenotype for genetic association studies. Association with SNP rs999662 indicates a potential role for the region containing the solute carrier family 12 member 3 (SLC12A3) gene in transcranial Doppler vasospasm following sub-arachnoid hemorrhage.