Neurocritical Care

, Volume 26, Issue 2, pp 213–224 | Cite as

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

  • Ruchira M. Jha
  • Ava M. Puccio
  • David O. Okonkwo
  • Benjamin E. Zusman
  • Seo-Young Park
  • Jessica Wallisch
  • Philip E. Empey
  • Lori A. Shutter
  • Robert S. B. Clark
  • Patrick M. Kochanek
  • Yvette P. Conley
Original Article



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.


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.


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).


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.


ABCC8 Cerebral edema Traumatic brain injury Single nucleotide polymorphism (SNP) Sulfonylurea receptor-1 (Sur1) 



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.

Compliance with Ethical Standards

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.


  1. 1.
    Dardiotis E, Paterakis K, Tsivgoulis G, Tsintou M, Hadjigeorgiou GF, Dardioti M, et al. AQP4 tag single nucleotide polymorphisms in patients with traumatic brain injury. J Neurotrauma. 2014;31:1920–6.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Dardiotis E, Fountas KN, Dardioti M, Xiromerisiou G, Kapsalaki E, Tasiou A, et al. Genetic association studies in patients with traumatic brain injury. Neurosurg Focus. 2010;28:E9.CrossRefPubMedGoogle Scholar
  3. 3.
    Narayan RK, Kishore PR, Becker DP, Ward JD, Enas GG, Greenberg RP, et al. Intracranial pressure: to monitor or not to monitor? A review of our experience with severe head injury. J Neurosurg. 1982;56:650–9.CrossRefPubMedGoogle Scholar
  4. 4.
    Liang F, Luo C, Xu G, Su F, He X, Long S, et al. Deletion of aquaporin-4 is neuroprotective during the acute stage of micro traumatic brain injury in mice. Neurosci Lett. 2015;598:29–35.CrossRefPubMedGoogle Scholar
  5. 5.
    Yao X, Uchida K, Papadopoulos MC, Zador Z, Manley GT, Verkman AS. Mildly reduced brain swelling and improved neurological outcome in aquaporin-4 knockout mice following controlled cortical impact brain injury. J Neurotrauma. 2015;32(19):1458–64.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Laird MD, Shields JS, Sukumari-Ramesh S, Kimbler DE, Fessler RD, Shakir B, et al. High mobility group box protein-1 promotes cerebral edema after traumatic brain injury via activation of toll-like receptor 4. Glia. 2014;62:26–38.CrossRefPubMedGoogle Scholar
  7. 7.
    Simard JM, Chen M, Tarasov KV, Bhatta S, Ivanova S, Melnitchenko L, et al. Newly expressed SUR1-regulated NC (Ca-ATP) channel mediates cerebral edema after ischemic stroke. Nat Med. 2006;12:433–40.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Patel AD, Meriggioli MN, Sanders DB, Gerzanich V, Geng Z, Simard JM. Glibenclamide reduces hippocampal injury and preserves rapid spatial learning in a model of traumatic brain injury. J Neuropathol Exp Neurol. 2010;69:1177–90.CrossRefPubMedGoogle Scholar
  9. 9.
    Simard JM, Kilbourne M, Tsymbalyuk O, Tosun C, Caridi J, Ivanova S, et al. Key role of sulfonylurea receptor 1 in progressive secondary hemorrhage after brain contusion. J Neurotrauma. 2009;26:2257–67.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Walcott BP, Kahle KT, Simard JM. Novel treatment targets for cerebral edema. Neurotherapeutics. 2011;9:65–72.CrossRefPubMedCentralGoogle Scholar
  11. 11.
    Huang L-Q, Zhu G-F, Deng Y-Y, Jiang W-Q, Fang M, Chen C-B, et al. Hypertonic saline alleviates cerebral edema by inhibiting microglia-derived TNF-α and IL-1β-induced Na–K–Cl Cotransporter up-regulation. J Neuroinflamm. 2014;11:102.CrossRefGoogle Scholar
  12. 12.
    Marmarou CR, Liang X, Abidi NH, Parveen S, Taya K, Henderson SC, et al. Selective vasopressin-1a receptor antagonist prevents brain edema, reduces astrocytic cell swelling and GFAP, V1aR and AQP4 expression after focal traumatic brain injury. Brain Res. 2014;1581:89–102.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Chen J-H, Yang L-K, Chen L, Wang Y-H, Wu Y, Jiang B-J, et al. Atorvastatin ameliorates early brain injury after subarachnoid hemorrhage via inhibition of AQP4 expression in rabbits. Int J Mol Med. 2016;37:1059–66.PubMedGoogle Scholar
  14. 14.
    Cousar JL, Conley YP, Willyerd FA, Sarnaik AA, Puccio AM, Empey PE, et al. Influence of ATP-binding cassette polymorphisms on neurological outcome after traumatic brain injury. Neurocrit Care. 2013;19:192–8.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Simard JM, Woo SK, Schwartzbauer GT, Gerzanich V. Sulfonylurea receptor 1 in central nervous system injury: a focused review. J Cereb Blood Flow Metab. 2012;32:1699–717.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Remedy Pharmaceuticals, Inc. A phase I randomized, double-blind, placebo-controlled study to assess the safety, tolerability, and pharmacokinetics of escalating doses of RP-1127 (glyburide for injection) in healthy male and female volunteers. 2016. p. 1–3.
  17. 17.
    Sheth KN, Elm JJ, Beslow LA, Sze GK, Kimberly WT. Glyburide advantage in malignant edema and stroke (GAMES-RP) trial: rationale and design. Neurocrit Care. 2016;24:132–9.CrossRefPubMedGoogle Scholar
  18. 18.
    Kimberly WT, Battey TWK, Pham L, Wu O, Yoo AJ, Furie KL, et al. Glyburide is associated with attenuated vasogenic edema in stroke patients. Neurocrit Care. 2014;20(2):193–201.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Sachidanandam R, Weissman D, Schmidt SC, Kakol JM, Stein LD, Marth G, et al. A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature. 2001;409:928–33.CrossRefPubMedGoogle Scholar
  20. 20.
    Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16:1215.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Conley YP, Okonkwo DO, Deslouches S, Alexander S, Puccio AM, Beers SR, et al. Mitochondrial polymorphisms impact outcomes after severe traumatic brain injury. J Neurotrauma. 2014;31:34–41.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Carter KW, McCaskie PA, Palmer LJ. JLIN: a java based linkage disequilibrium plotter. BMC Bioinform. 2006;7:60.CrossRefGoogle Scholar
  23. 23.
    Eisenberg HM, Gary HE, Aldrich EF, Saydjari C, Turner B, Foulkes MA, et al. Initial CT findings in 753 patients with severe head injury. A report from the NIH Traumatic Coma Data Bank. J Neurosurg. 1990;73:688–98.CrossRefPubMedGoogle Scholar
  24. 24.
    Miller MT, Pasquale M, Kurek S, White J, Martin P, Bannon K, et al. Initial head computed tomographic scan characteristics have a linear relationship with initial intracranial pressure after trauma. J Trauma Acute Care Surg. 2004;56:967–73.CrossRefGoogle Scholar
  25. 25.
    Dardiotis E, Jagiella J, Xiromerisiou G, Dardioti M, Vogiatzi C, Urbanik A, et al. Angiotensin-converting enzyme tag single nucleotide polymorphisms in patients with intracerebral hemorrhage. Pharmacogenet Genom. 2011;21:136–41.CrossRefGoogle Scholar
  26. 26.
    Balding DJ. A tutorial on statistical methods for population association studies. Nat Rev Genet. 2006;7:781–91.CrossRefPubMedGoogle Scholar
  27. 27.
    Narum SR. Beyond Bonferroni: less conservative analyses for conservation genetics. Conserv Genet. 2006;7:783–7.CrossRefGoogle Scholar
  28. 28.
    Martínez-Valverde T, Vidal-Jorge M, Martinez-Saez E, Castro L, Arikan F, Cordero E, et al. Sulfonylurea receptor 1 in humans with post-traumatic brain contusions. J Neurotrauma. 2015;32:1478–87.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Jha R, Puccio A, Chou S, Chang C-C, Wallisch J, Molyneaux B, et al. Sulfonylurea receptor-1 as a novel biomarker for cerebral edema in patients with severe traumatic brain injury (S46.001). Neurology. 2016;86(S46):001.Google Scholar
  30. 30.
    Flanagan SE, Clauin S, Bellanné-Chantelot C, de Lonlay P, Harries LW, Gloyn AL, et al. Update of mutations in the genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and sulfonylurea receptor 1 (ABCC8) in diabetes mellitus and hyperinsulinism. Hum Mutat. 2008;30:170–80.CrossRefGoogle Scholar
  31. 31.
    Proverbio MC, Mangano E, Gessi A, Bordoni R, Spinelli R, Asselta R, et al. Whole genome SNP genotyping and exome sequencing reveal novel genetic variants and putative causative genes in congenital hyperinsulinism. PLoS ONE. 2013;8(7):e68740.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Aittoniemi J, Fotinou C, Craig TJ, de Wet H, Proks P, Ashcroft FM. SUR1: a unique ATP-binding cassette protein that functions as an ion channel regulator. Philos Trans R Soc B Biol Sci. 2009;364:257–67.CrossRefGoogle Scholar
  33. 33.
    Denton JS, Jacobson DA. Channeling dysglycemia: ion-channel variations perturbing glucose homeostasis. Trends Endocrinol Metab. 2012;23:41–8.CrossRefPubMedGoogle Scholar
  34. 34.
    Aguilar-Bryan L, Bryan J. Molecular biology of adenosine triphosphate-sensitive potassium channels. Endocr Rev. 1999;20:101–35.PubMedGoogle Scholar
  35. 35.
    Hardy OT, Hernandez-Pampaloni M, Saffer JR, Suchi M, Ruchelli E, Zhuang H, et al. Diagnosis and localization of focal congenital hyperinsulinism by 18F-fluorodopa PET scan. J Pediatr. 2007;150:140–5.CrossRefPubMedGoogle Scholar
  36. 36.
    Nestorowicz A, Glaser B, Wilson BA, Shyng S-L, Nichols CG, Stanley CA, et al. Genetic heterogeneity in familial hyperinsulinism. Hum Mol Genet. 1998;7:1119–28.CrossRefPubMedGoogle Scholar
  37. 37.
    Glaser B, Ryan F, Donath M, Landau H, Stanley CA. Hyperinsulinism caused by paternal-specific inheritance of a recessive mutation in the sulfonylurea-receptor gene. Diabetes. 1999;48:1652–7.CrossRefPubMedGoogle Scholar
  38. 38.
    Stanley CA, Thornton PS, Ganguly A, MacMullen C, Underwood P, Bhatia P, et al. Preoperative evaluation of infants with focal or diffuse congenital hyperinsulinism by intravenous acute insulin response tests and selective pancreatic arterial calcium stimulation. J Clin Endocrinol Metab. 2004;89:288–96.CrossRefPubMedGoogle Scholar
  39. 39.
    Knight JC. Functional implications of genetic variation in non-coding DNA for disease susceptibility and gene regulation. Clin Sci. 2003;104:493–501.CrossRefPubMedGoogle Scholar
  40. 40.
    Ritter AC, Kammerer CM, Brooks MM, Conley YP, Wagner AK. Genetic variation in neuronal glutamate transport genes and associations with posttraumatic seizure. Epilepsia. 2016;57:984–93.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Ruchira M. Jha
    • 1
    • 2
    • 3
    • 4
    • 10
  • Ava M. Puccio
    • 2
  • David O. Okonkwo
    • 2
  • Benjamin E. Zusman
    • 2
  • Seo-Young Park
    • 5
    • 6
  • Jessica Wallisch
    • 1
    • 4
  • Philip E. Empey
    • 8
    • 10
  • Lori A. Shutter
    • 1
    • 2
    • 3
  • Robert S. B. Clark
    • 1
    • 4
    • 7
    • 9
  • Patrick M. Kochanek
    • 1
    • 4
    • 7
    • 9
    • 10
  • Yvette P. Conley
    • 11
    • 12
    • 10
  1. 1.Department of Critical Care Medicine, School of MedicineUniversity of PittsburghPittsburghUSA
  2. 2.Department of Neurosurgery, School of MedicineUniversity of PittsburghPittsburghUSA
  3. 3.Department of Neurology, School of MedicineUniversity of PittsburghPittsburghUSA
  4. 4.Safar Center for Resuscitation Research, School of MedicineUniversity of PittsburghPittsburghUSA
  5. 5.Department of Medicine, School of MedicineUniversity of PittsburghPittsburghUSA
  6. 6.Department of Biostatistics, School of Public HealthUniversity of PittsburghPittsburghUSA
  7. 7.Department of Critical Care Medicine, School of MedicineUniversity of PittsburghPittsburghUSA
  8. 8.Department of Pharmacy and Therapeutics, School of PharmacyUniversity of PittsburghPittsburghUSA
  9. 9.Department of Anesthesiology, School of MedicineUniversity of PittsburghPittsburghUSA
  10. 10.Clinical and Translational Science Institute, School of MedicineUniversity of PittsburghPittsburghUSA
  11. 11.School of NursingUniversity of PittsburghPittsburghUSA
  12. 12.Department of Human GeneticsUniversity of PittsburghPittsburghUSA

Personalised recommendations