A pilot study on the impact of dopamine, serotonin, and brain-derived neurotrophic factor genotype on long-term functional outcomes after subarachnoid hemorrhage

Abstract

Objectives:Many that survive an aneurysmal subarachnoid hemorrhage experience lasting physical disability, which might be improved by medications with effects on the dopaminergic, serotonergic, and brain-derived neurotrophic factor neurotransmitter systems. But it is not clear which patients are most likely to benefit from these therapies. The purpose of this pilot study was to explore the relationship of genetic polymorphisms in these pathways with 12-month functional outcomes after aneurysmal subarachnoid hemorrhage.Methods:Subjects were recruited at the time of admission as a part of a larger parent study. Genotypes were generated using the Affymetrix genome-wide human single-nucleotide polymorphism array 6.0. Those within dopaminergic, serotonergic, and brain-derived neurotrophic factor pathways were analyzed for associations with functional outcomes at 12 months post aneurysmal subarachnoid hemorrhage using the Glasgow Outcome Scale and the Modified Rankin Scale.Results:The 154 subjects were 55.8 ± 11.3 years old and 74% female; they had Fisher scores of 2.95 ± 0.67, Hunt/Hess scores of 2.66 ± 1.13, and admission Glasgow Coma Scale scores of 12.52 ± 3.79. Single-nucleotide polymorphisms in the serotonin receptor genes 1B and 1E and dopamine receptor D2 were associated with greater disability (odds ratio: 3.88–3.25, confidence interval: 1.01–14.77), while single-nucleotide polymorphisms in the serotonin receptor genes 2A and 2C and dopamine receptor D5 conferred a risk of poor recovery (odds ratio: 3.31–2.32, confidence interval: 1.00–10.80). Single-nucleotide polymorphisms within the same serotonin genes, and within the dopamine receptor gene D2, were associated with greater recovery after aneurysmal subarachnoid hemorrhage (odds ratio: 0.17–0.34, confidence interval: 0.05–0.89).Conclusions:These data demonstrate that there may be an association between genetic factors and functional outcomes post stroke.

Identification of upregulated NF-κB inhibitor alpha and IRAK3 targeting lncRNA following intracranial aneurysm rupture-induced subarachnoid hemorrhage

“…Recently, the interaction between p75 neurotrophin receptor (p75NTR) and the proapoptotic BH3-only protein NIX was identified by Shen et al, who argued that the interaction of p75NTR and protein NIX were crucial for the p75NTR-mediated neuron apoptosis in intracerebral hemorrhage [39]. Many studies have also highlighted that neurotrophic factors were crucial for the neurological recovery following SAH [40,41]. A Fig.…”

Enhancing Research Through the Use of the Genotype-Tissue Expression (GTEx) Database

“…Our exemplar focuses specifically on the dopamine receptor type 2 ( DRD2 ), a gene known to have high expression in neural tissues. Genetic variations in this gene have been associated with a variety of conditions including stroke ( Stanfill et al, 2016 , 2017 ), Parkinson’s disease ( McGuire et al, 2011 ), weight gain ( Stanfill, Hathaway, et al, 2015 ; Stanfill, Conley, et al, 2015 ) and binge eating ( Kessler et al, 2016 ), with alcohol consumption ( Clarke et al, 2017 ), and substance addiction ( Buhler et al, 2015 ). Our work to date has focused mainly on genotypic changes in DRD2 , but it is reasonable to hypothesize that alterations in the sequence could alter this expression in the brain, whether they are directly involved in the coding itself, or whether these variants could act as regulatory variants that alter gene expression and/or splicing ( Kaalund et al, 2014 ; Stanfill & Cao, 2020 ; Zhang et al, 2007 ).…”

“…As mentioned previously, our team’s work is in neurologic injury and disease, and DRD2 variations are well-known to be associated with these conditions ( Buhler et al, 2015 ; Clarke et al, 2017 ; McGuire et al, 2011 ; Stanfill & Cao, 2020 ; Stanfill et al, 2016 , 2017 ). The information provided by the GTEx portal has enhanced our program of research by demonstrating how DRD2 is expressed across several different brain tissues that cannot be easily accessed in our living subjects.…”