@article{ref1,
title="Regionally clustered <i>ABCC8</i> polymorphisms in a prospective cohort predict cerebral oedema and outcome in severe traumatic brain injury",
journal="Journal of neurology, neurosurgery, and psychiatry",
year="2018",
author="Jha, Ruchira Menka and Koleck, Theresa A. and Puccio, Ava M. and Okonkwo, David O. and Park, Seo-Young and Zusman, Benjamin E. and Clark, Robert S. B. and Shutter, Lori A. and Wallisch, Jessica S. and Empey, Philip E. and Kochanek, Patrick M. and Conley, Yvette P.",
volume="89",
number="11",
pages="1152-1162",
abstract="OBJECTIVE: <i>ABCC8</i> 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 <i>ABCC8</i> tag single-nucleotide polymorphisms predicted oedema and outcome in TBI. <br><br>METHODS: DNA was extracted from 485 prospectively enrolled patients with severe TBI. 410 were analysed after quality control. <i>ABCC8</i> tag single-nucleotide polymorphisms (SNPs) were identified (Hapmap, r<sup>2</sup>>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. <br><br>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. <br><br>CONCLUSIONS: This study identifies four <i>ABCC8</i> 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.<br><br>© 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.<p /> <p>Language: en</p>",
language="en",
issn="0022-3050",
doi="10.1136/jnnp-2017-317741",
url="http://dx.doi.org/10.1136/jnnp-2017-317741"
}