OBJECTIVETo study whether endothelial nitric oxide synthase gene (eNOS) polymorphisms is implicated in the development of cerebral vasospasm following subarachnoid hemorrhage.

METHODSThree groups of patients with subarachnoid hemorrhage were selected to test this hypothesis, including 98 patients with cerebral vasospasm following aneurysmal subarachnoid hemorrhage (ASAH), 96 with cerebral vasospasm following traumatic subarachnoid hemorrhage (TSAH), and 195 patients without cerebral vasospasm following aneurysmal or traumatic subarachnoid hemorrhage. The parents of 194 patients and 100 control subjects were also examined for transmission disequilibrium test according to a family-based study design to test the associations.

RESULTSWe examined four eNOS gene polymorphisms, and two of these polymorphisms, the T to C substitution in the promoter at position -786 and the a-deletion/b-insertion in intron 4, were found to associate with cerebral vasospasm in subarachnoid hemorrhage in the case-control comparisons. For the former polymorphism, the risk of cerebral vasospasm was higher in C allele homozygotes than in the other two genotypes (odds ratio: 2.8, 95% CI: 1.4 to 5.6); for the latter polymorphism, the a-deletion carriers were exposed to a increased risk (odds ratio: 2.3, 95% CI: 1.3 to 4.0) in comparison with the noncarriers. The two polymorphisms were analyzed together as haplotypes in a family-based study using the transmission disequilibrium test. The C/a-deletion haplotype was transmitted from the heterozygous parents to cases of cerebral vasospasm in subarachnoid hemorrhage with a significantly higher frequency than expected (P=0.005).

CONCLUSIONThe findings of the case-control and family-based studies clearly demonstrate that DNA sequence differences in eNOS gene influence the risk of cerebral vasospasm in subarachnoid hemorrhage.