Research Reports - Impact of genetic variation on hormone levels and outcome after traumatic brain injury

J Neurotrauma. 2013 Aug 15;30(16):1415-25

Garringer JA, Niyonkuru C, McCullough EH, Loucks T, Dixon CE, Conley YP, Berga S, Wagner AK

Although experimental traumatic brain injury (TBI) studies support
estradiol as a neuroprotectant and potent stimulator of neuroplasticity, clinical
studies suggest a negative association between endogenous estradiol profiles and
mortality/poor outcomes. However, no studies have evaluated associations with
cerebral spinal fluid (CSF) hormone profiles and aromatase gene (cytochrome P450
[CYP]19A1) variability on clinical TBI outcomes. We evaluated 110 adults with
severe TBI. Average and daily estradiol, testosterone, and estradiol/testosterone
ratios (E2:T) were measured using CSF and serum samples and compared to healthy
controls. Eighteen tagging and four functional single-nucleotide polymorphisms
(SNPs) for CYP19A1 were genotyped and compared to hormones, acute mortality, and
Glasgow Outcome Scale (GOS) scores 6 months post-TBI. TBI subjects had lower CSF
estradiol over time versus controls. CSF testosterone was initially high, but
declined over time. E2/T ratios were initially low, compared to controls, but
rose over time. Higher mean E2/T ratio in bivariate analysis was associated with
lower mortality (p=0.019) and better GOS-6 scores (p=0.030). rs2470152 influenced
CSF E2/T ratio and also serum and CSF testosterone (p≤0.05 all comparisons).
Multiple-risk SNPs rs2470152, rs4646, and rs2470144 were associated with worse
GOS-6 scores (p≤0.05, all comparisons), and those with>1 risk SNP variant had a
higher risk for poor outcome, compared with those with ≤1 risk variant. TBI
results in low CSF estradiol and dynamic CSF testosterone and E2/T ratio. In
contrast to clinical serum hormone studies, higher CSF E2/T ratio was associated
with better outcome. Further, genetic variation in CYP19A1 influences both
hormone dynamics and outcome post-TBI.

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