Neurocritical Care

, Volume 26, Issue 2, pp 213–224

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

DOI: 10.1007/s12028-016-0309-z

Cite this article as:
Jha, R.M., Puccio, A.M., Okonkwo, D.O. et al. Neurocrit Care (2017) 26: 213. doi:10.1007/s12028-016-0309-z

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.

Keywords

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

Funding information

Funder NameGrant NumberFunding Note
National Institutes of Health
  • KL2 TR000146
  • R00 NR013176
  • R01 NR013342

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

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