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

Authors

• Ruchira Menka Jha, Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.Follow
• Theresa A. Koleck, School of Nursing, Columbia University, New York, USA.
• Ava M. Puccio, Department of Neurosurgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
• David O. Okonkwo, Department of Neurosurgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
• Seo-Young Park, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
• Benjamin E. Zusman, Department of Neurosurgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
• Robert S. Clark, Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
• Lori A. Shutter, Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
• Jessica S. Wallisch, Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
• Philip E. Empey, Clinical and Translational Science Institute, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
• Patrick M. Kochanek, Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
• Yvette P. Conley, Clinical and Translational Science Institute, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Document Type

Article

Abstract

OBJECTIVE: 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 tag single-nucleotide polymorphisms predicted oedema and outcome in TBI. METHODS: DNA was extracted from 485 prospectively enrolled patients with severe TBI. 410 were analysed after quality control. tag single-nucleotide polymorphisms (SNPs) were identified (Hapmap, r>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. RESULTS: Wild-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. CONCLUSIONS: This study identifies four 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.

Medical Subject Headings

Adolescent; Adult; Aged; Alleles; Brain Edema (etiology, genetics); Brain Injuries, Traumatic (complications, genetics); Female; Gene Frequency; Genotype; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Prognosis; Prospective Studies; Recovery of Function; Sulfonylurea Receptors (genetics); Young Adult

Publication Date

11-1-2018

Publication Title

Journal of neurology, neurosurgery, and psychiatry

E-ISSN

1468-330X

Volume

89

Issue

11

First Page

1152

Last Page

1162

PubMed ID

29674479

Digital Object Identifier (DOI)

10.1136/jnnp-2017-317741

Recommended Citation

Jha, Ruchira Menka; Koleck, Theresa A.; Puccio, Ava M.; Okonkwo, David O.; Park, Seo-Young; Zusman, Benjamin E.; Clark, Robert S.; Shutter, Lori A.; Wallisch, Jessica S.; Empey, Philip E.; Kochanek, Patrick M.; and Conley, Yvette P., "Regionally clustered polymorphisms in a prospective cohort predict cerebral oedema and outcome in severe traumatic brain injury" (2018). Neurology. 1362.
https://scholar.barrowneuro.org/neurology/1362