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Regionally clustered ABCC8 polymorphisms in a prospective cohort predict cerebral oedema and outcome in severe traumatic brain injury

Journal of neurology, neurosurgery and psychiatry, 2018-11, Vol.89 (11), p.1152-1162 [Peer Reviewed Journal]

Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted. ;2018 Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted. ;ISSN: 0022-3050 ;EISSN: 1468-330X ;DOI: 10.1136/jnnp-2017-317741 ;PMID: 29674479

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Title:
Regionally clustered ABCC8 polymorphisms in a prospective cohort predict cerebral oedema and outcome in severe traumatic brain injury
Author: Jha, Ruchira Menka ; Koleck, Theresa A ; Puccio, Ava M ; Okonkwo, David O ; Park, Seo-Young ; Zusman, Benjamin E ; Clark, Robert S B ; Shutter, Lori A ; Wallisch, Jessica S ; Empey, Philip E ; Kochanek, Patrick M ; Conley, Yvette P
Subjects: Adolescent ; Adult ; Aged ; Alleles ; Bioinformatics ; Brain Edema - etiology ; Brain Edema - genetics ; Brain Injuries, Traumatic - complications ; Brain Injuries, Traumatic - genetics ; Brain research ; Clinical trials ; Deoxyribonucleic acid ; Diabetes ; DNA ; Edema ; Female ; Gene Frequency ; Genes ; Genomes ; Genotype ; Genotype & phenotype ; Humans ; Male ; Middle Aged ; Polymorphism ; Polymorphism, Single Nucleotide ; Prognosis ; Prospective Studies ; Proteins ; Quality control ; Recovery of Function ; Sulfonylurea Receptors - genetics ; Traumatic brain injury ; Variance analysis ; Young Adult
Is Part Of: Journal of neurology, neurosurgery and psychiatry, 2018-11, Vol.89 (11), p.1152-1162
Description: Objective ABCC8 encodes sulfonylurea receptor 1, a key regulatory protein of cerebral oedema in many neurological disorders including traumatic brain injury (TBI). Sulfonylurea-receptor-1 inhibition has been promising in ameliorating cerebral oedema in clinical trials. We evaluated whether ABCC8 tag single-nucleotide polymorphisms predicted oedema and outcome in TBI.MethodsDNA was extracted from 485 prospectively enrolled patients with severe TBI. 410 were analysed after quality control. ABCC8 tag single-nucleotide polymorphisms (SNPs) were identified (Hapmap, r2>0.8, minor-allele frequency >0.20) and sequenced (iPlex-Gold, MassArray). Outcomes included radiographic oedema, intracranial pressure (ICP) and 3-month Glasgow Outcome Scale (GOS) score. Proxy SNPs, spatial modelling, amino acid topology and functional predictions were determined using established software programs.ResultsWild-type rs7105832 and rs2237982 alleles and genotypes were associated with lower average ICP (β=−2.91, p=0.001; β=−2.28, p=0.003) and decreased radiographic oedema (OR 0.42, p=0.012; OR 0.52, p=0.017). Wild-type rs2237982 also increased favourable 3-month GOS (OR 2.45, p=0.006); this was partially mediated by oedema (p=0.03). Different polymorphisms predicted 3-month outcome: variant rs11024286 increased (OR 1.84, p=0.006) and wild-type rs4148622 decreased (OR 0.40, p=0.01) the odds of favourable outcome. Significant tag and concordant proxy SNPs regionally span introns/exons 2–15 of the 39-exon gene.ConclusionsThis study identifies four ABCC8 tag SNPs associated with cerebral oedema and/or outcome in TBI, tagging a region including 33 polymorphisms. In polymorphisms predictive of oedema, variant alleles/genotypes confer increased risk. Different variant polymorphisms were associated with favourable outcome, potentially suggesting distinct mechanisms. Significant polymorphisms spatially clustered flanking exons encoding the sulfonylurea receptor site and transmembrane domain 0/loop 0 (juxtaposing the channel pore/binding site). This, if validated, may help build a foundation for developing future strategies that may guide individualised care, treatment response, prognosis and patient selection for clinical trials.
Publisher: England: BMJ Publishing Group LTD
Language: English
Identifier: ISSN: 0022-3050
EISSN: 1468-330X
DOI: 10.1136/jnnp-2017-317741
PMID: 29674479
Source: ProQuest One Psychology
AUTh Library subscriptions: ProQuest Central
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Regionally clustered ABCC8 polymorphisms in a prospective cohort predict cerebral oedema and outcome in severe traumatic brain injury

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