TY  - JOUR
PY  - 2018//
TI  - Regionally clustered <i>ABCC8</i> polymorphisms in a prospective cohort predict cerebral oedema and outcome in severe traumatic brain injury
JO  - Journal of neurology, neurosurgery, and psychiatry
A1  - Jha, Ruchira Menka
A1  - Koleck, Theresa A.
A1  - Puccio, Ava M.
A1  - Okonkwo, David O.
A1  - Park, Seo-Young
A1  - Zusman, Benjamin E.
A1  - Clark, Robert S. B.
A1  - Shutter, Lori A.
A1  - Wallisch, Jessica S.
A1  - Empey, Philip E.
A1  - Kochanek, Patrick M.
A1  - Conley, Yvette P.
SP  - 1152
EP  - 1162
VL  - 89
IS  - 11
N2  - 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>
LA  - en
SN  - 0022-3050
UR  - http://dx.doi.org/10.1136/jnnp-2017-317741
ID  - ref1
ER  -