title: Impact of aromatase genetic variation on hormone levels and global outcome after severe TBI.
abstract: 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.
authors.affiliation: University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Garringer
authors.forename: Christian
authors.initials: C
authors.lastname: Niyonkuru
authors.forename: Emily H
authors.initials: EH
authors.lastname: McCullough
authors.forename: Tammy
authors.initials: T
authors.lastname: Loucks
authors.forename: C Edward
authors.initials: CE
authors.lastname: Dixon
authors.forename: Yvette P
authors.initials: YP
authors.lastname: Conley
authors.forename: Sarah
authors.initials: S
authors.lastname: Berga
authors.forename: Amy K
authors.initials: AK
authors.lastname: Wagner
mesh_terms: D000328:Adult; D001141:Aromatase / Q000235:genetics*; D015415:Biomarkers / Q000097:blood / Q000134:cerebrospinal fluid; D001930:Brain Injuries / Q000097:blood / Q000134:cerebrospinal fluid* / Q000235:genetics*; D004958:Estradiol / Q000097:blood* / Q000134:cerebrospinal fluid*; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012720:Severity of Illness Index; D013739:Testosterone / Q000097:blood / Q000134:cerebrospinal fluid*; D055815:Young Adult
chemical_list: D015415:Biomarkers; D013739:Testosterone; D004958:Estradiol; D001141:Aromatase; C561410:CYP19A1 protein, human
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