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ABCC8 Single Nucleotide Polymorphisms are Associated with Cerebral Edema in Severe TBI

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Abstract

Objective

Cerebral edema (CE) in traumatic brain injury (TBI) is the consequence of multiple underlying mechanisms and is associated with unfavorable outcomes. Genetic variability in these pathways likely explains some of the clinical heterogeneity observed in edema development. A role for sulfonylurea receptor-1 (Sur1) in CE is supported. However, there are no prior studies examining the effect of genetic variability in the Sur1 gene (ABCC8) on the development of CE. We hypothesize that ABCC8 single nucleotide polymorphisms (SNPs) are predictive of CE.

Methods

DNA was extracted from 385 patients. SNPs in ABCC8 were genotyped using the Human Core Exome v1.2 (Illumina). CE measurements included acute CT edema, mean and peak intracranial pressure (ICP), and need for decompressive craniotomy.

Results

Fourteen SNPs with minor allele frequency >0.2 were identified. Four SNPS rs2283261, rs3819521, rs2283258, and rs1799857 were associated with CE measures. In multiple regression models, homozygote-variant genotypes in rs2283261, rs3819521, and rs2283258 had increased odds of CT edema (OR 2.45, p = 0.007; OR 2.95, p = 0.025; OR 3.00, p = 0.013), had higher mean (β = 3.13, p = 0.000; β = 2.95, p = 0.005; β = 3.20, p = 0.008), and peak ICP (β = 8.00, p = 0.001; β = 7.64, p = 0.007; β = 6.89, p = 0.034). The homozygote wild-type genotype of rs1799857 had decreased odds of decompressive craniotomy (OR 0.47, p = 0.004).

Conclusions

This is the first report assessing the impact of ABCC8 genetic variability on CE development in TBI. Minor allele ABCC8 SNP genotypes had increased risk of CE, while major SNP alleles were protective—potentially suggesting an evolutionary advantage. These findings could guide risk stratification, treatment responders, and the development of novel targeted or gene-based therapies against CE in TBI and other neurological disorders.

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Funding

We are grateful to NIH Grant Nos. KL2 TR000146 (RMJ), R00 NR013176 (YPC), R01 NR013342 (YPC) and T32 HD040686 (JW) for their generous support.

Author Contributions

Ruchira M. Jha was involved in study concept, design, data analysis and interpretation, and manuscript generation. Ava M. Puccio, David O. Okonkwo, and Benjamin E. Zusman were involved in acquisition of data. Seo-Young Park was involved in statistical analysis review. Jessica Wallisch, Philip E. Empey, Lori A. Shutter, and Robert S. B. Clark were involved in content expertise and critical revision of the manuscript. Patrick M. Kochanek was involved in study concept, content expertise, and critical revision of manuscript. Yvette P. Conley was involved in study concept, data acquisition and interpretation, supervision, and critical revision of manuscript.

Author information

Authors and Affiliations

  1. Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, 3550 Terrace Street, Pittsburgh, PA, 15261, USA

    Ruchira M. Jha, Jessica Wallisch, Lori A. Shutter, Robert S. B. Clark & Patrick M. Kochanek

  2. Department of Neurosurgery, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Ruchira M. Jha, Ava M. Puccio, David O. Okonkwo, Benjamin E. Zusman & Lori A. Shutter

  3. Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Ruchira M. Jha & Lori A. Shutter

  4. Safar Center for Resuscitation Research, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Ruchira M. Jha, Jessica Wallisch, Robert S. B. Clark & Patrick M. Kochanek

  5. Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Seo-Young Park

  6. Department of Biostatistics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA

    Seo-Young Park

  7. Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Robert S. B. Clark & Patrick M. Kochanek

  8. Department of Pharmacy and Therapeutics, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA

    Philip E. Empey

  9. Department of Anesthesiology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Robert S. B. Clark & Patrick M. Kochanek

  10. Clinical and Translational Science Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Ruchira M. Jha, Philip E. Empey, Patrick M. Kochanek & Yvette P. Conley

  11. School of Nursing, University of Pittsburgh, Pittsburgh, PA, USA

    Yvette P. Conley

  12. Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA

    Yvette P. Conley

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  1. Ruchira M. Jha
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Correspondence to Ruchira M. Jha.

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Conflict of interest

Ruchira M. Jha, Ava M. Puccio, David O. Okonkwo, Benjamin E. Zusman, Seo-Young Park, Jessica Wallisch, and Philip E. Empey report no disclosures. Lori A. Shutter reports DOD Grant W81XWH-08-2-0159 and NINDS Grant 1U10NS069498. This funding was not related to this study, and there are no conflicts of interest. Robert S. B. Clark reports no disclosures. Patrick M. Kochanek has grants from NIH and the U.S. DoD. He is editor-in-chief of the journal Pediatric Critical Care Medicine and receives an editor stipend. He is one of the editors of the Textbook of Critical Care and receives royalties for that work. He is a co-author of several US patents or provisional patents (below): United States Patent: US 8,628,512 B2 Title Method of Inducing EPR Following Cardiopulmonary Arrest. Filing Date 6/22/05. Inventors PM Kochanek, SA Tisherman, X Wu, SW Stezoski, LJ Yaffe. United States Provisional Patent Title Compositions and Methods for Identifying Subjects at Risk for Traumatic Brain Injury. Serial No 62/113,292. Filing Date February 6, 2015. Inventors RP Berger, PM Kochanek, BJ Pak, PT Smith, MD Kolesnikova. United States Invention Disclosure Title Small Molecule Inhibitors of RNA Binding MOTIF (RBM) Proteins for the Treatment of Acute Cellular Injury. University of Pittsburgh. Filing Date November 13, 2014. Inventors TC Jackson, J Verrier, PM Kochanek. United States Invention Disclosure Title Method to improve neurologic outcomes in temperature managed patients. Application No. 62/164,205. Country United States. Innovators Travis C. Jackson (University of Pittsburgh); Patrick M. Kochanek. Yvette P. Conley reports no disclosures.

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Jha, R.M., Puccio, A.M., Okonkwo, D.O. et al. ABCC8 Single Nucleotide Polymorphisms are Associated with Cerebral Edema in Severe TBI. Neurocrit Care 26, 213–224 (2017). https://doi.org/10.1007/s12028-016-0309-z

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