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Research paper
Regionally clustered ABCC8 polymorphisms in a prospective cohort predict cerebral oedema and outcome in severe traumatic brain injury
  1. Ruchira Menka Jha1,2,3,4,5,
  2. Theresa A Koleck6,
  3. Ava M Puccio3,
  4. David O Okonkwo3,
  5. Seo-Young Park7,8,
  6. Benjamin E Zusman3,
  7. Robert S B Clark1,4,9,
  8. Lori A Shutter1,2,3,
  9. Jessica S Wallisch1,4,
  10. Philip E Empey5,10,
  11. Patrick M Kochanek1,4,5,9,
  12. Yvette P Conley5,11,12
  1. 1Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  2. 2Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  3. 3Department of Neurosurgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  4. 4Safar Center for Resuscitation Research, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  5. 5Clinical and Translational Science Institute, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  6. 6School of Nursing, Columbia University, New York, USA
  7. 7Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  8. 8Department of Biostatistics, School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  9. 9Department of Anesthesia, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  10. 10Department of Pharmacy and Therapeutics, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  11. 11School of Nursing, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  12. 12Department of Human Genetics, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  1. Correspondence to Dr Ruchira Menka Jha, Department of Critical Care Medicine, Neurology, Neurosurgery, University of Pittsburgh, Pittsburgh, PA 15260, USA; jharm3{at}upmc.edu

Abstract

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.

Methods DNA 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.

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 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.

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Footnotes

  • Contributors RMJ was involved in study concept, design, data analysis and interpretation, and manuscript generation. TAK was involved with statistical analysis and haplotype generation and analysis. AMP, DOO and BEZ were involved in acquisition of data and patient samples. S-YP was involved in statistical analysis and review. JSW, PEE, LAS and RSBC were involved in content expertise and critical revision of the manuscript. PMK was involved in study concept, content expertise, supervision and critical review of the manuscript. YPC was involved in study concept, design, data acquisition and interpretation, supervision and critical revision of the manuscript.

  • Funding This study was funded by U.S. Department of Health and Human Services. RMJ discloses funding by the following NIH grants: T-32HL007820, NCATS KL2-TR000146, NCATS KL2-TR001856 and NINDS K23NS101036. TAK discloses NIH funding NINR F31NR014590 and T32NR007969. AMP discloses funding by the NIH grant NINR R00 NR013176. JSW discloses funding by the NIH grant NICHD T32-HD040686. PEE reports no disclosures. PMK discloses funding by the NIH grant 1R01NS087978-01. YPC discloses funding by the NIH grant NINR R01NR013342. RMJ have received a UPP Foundation Award.

  • Competing interests The rest of the authors (DOO, S-YP, BEZ, RSBC, LAS and PEE) report no disclosures.

  • Patient consent Not required.

  • Ethics approval University of Pittsburgh Institutional Review Board.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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