POLYMORPHISMS OF THE ENDOTHELIAL NITRIC OXIDE SYNTHASE (ENOS GLU298ASP, RS1799983) AND METHYLENETETRAHYDROFOLATE REDUCTASE (MTHFR C677T, RS1801133) GENES, PLASMA HOMOCYSTEINE AND CEREBROVASCULAR COMPLICATIONS AFTER TRAUMATIC BRAIN INJURY
DOI:
https://doi.org/10.17605/Keywords:
Traumatic brain injury; gene polymorphism; endothelial nitric oxide synthase; methylenetetrahydrofolate reductase; homocysteine; cerebral vasospasm; rs1799983; rs1801133; GOS-E.Abstract
injury after traumatic brain injury (TBI). Two functional variants act on this axis: the endothelial nitric oxide synthase polymorphism eNOS Glu298Asp (rs1799983), which lowers nitric oxide bioavailability, and the methylenetetrahydrofolate reductase polymorphism MTHFR C677T (rs1801133), which produces a thermolabile enzyme and raises plasma homocysteine, an amino acid that is itself toxic to the endothelium. We aimed to determine the distribution of these variants in patients with TBI, to relate them to plasma homocysteine as a downstream read-out, and to assess their association with cerebrovascular and endothelial complications and 6-month functional outcome.
Methods. Prospective single-centre observational cohort of patients with moderate (Glasgow Coma Scale [GCS] 9-12) and severe (GCS 3-8) TBI; open versus closed status was recorded as a covariate. eNOS rs1799983 and MTHFR rs1801133 were genotyped and tested for Hardy-Weinberg equilibrium. Plasma homocysteine was measured serially and the peak value used. Cerebrovascular and endothelial complications (cerebral vasospasm, delayed cerebral ischaemia, new ischaemic lesions on imaging, and thrombotic events) were recorded by predefined criteria; outcome was assessed with the Extended Glasgow Outcome Scale (GOS-E) at discharge and at 6 months. Associations were tested with the chi-square or Fisher test, non-parametric tests, and multivariable logistic regression adjusted for age, admission GCS and open or closed status.
Results. In this preliminary interim analysis (112 patients, 120 controls), the MTHFR 677 TT genotype was associated with higher plasma homocysteine and a higher incidence of cerebrovascular and endothelial complications (adjusted OR 4.6, 95% CI 1.2 to 17.9), and eNOS 298Asp carriers showed a similar trend. Peak homocysteine and the combined high-risk genotype were independent predictors in a multivariable model (area under the ROC curve 0.76). Full results are shown in Tables 1 to 5; the values are preliminary and will be finalised on completion of recruitment.
Conclusion. Polymorphisms of eNOS and MTHFR, integrated through plasma homocysteine, are candidate molecular markers for the risk of cerebrovascular and endothelial complications after TBI. Adequately powered, multicentre confirmation is required.
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