ABCC8 Single Nucleotide Polymorphisms are Associated with Cerebral Edema in Severe TBI.
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.
Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, 3550 Terrace Street, Pittsburgh, PA, 15261, USA. ruchirajha@gmail.com.|Department of Neurosurgery, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. ruchirajha@gmail.com.|Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. ruchirajha@gmail.com.|Safar Center for Resuscitation Research, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. ruchirajha@gmail.com.|Clinical and Translational Science Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. ruchirajha@gmail.com.
Ruchira M
0000-0002-3047-7649
RM
Jha
Department of Neurosurgery, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Ava M
AM
Puccio
Department of Neurosurgery, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
David O
DO
Okonkwo
Department of Neurosurgery, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Benjamin E
BE
Zusman
Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.|Department of Biostatistics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
Seo-Young
SY
Park
Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, 3550 Terrace Street, Pittsburgh, PA, 15261, USA.|Safar Center for Resuscitation Research, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Jessica
J
Wallisch
Department of Pharmacy and Therapeutics, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA.|Clinical and Translational Science Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Philip E
PE
Empey
Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, 3550 Terrace Street, Pittsburgh, PA, 15261, USA.|Department of Neurosurgery, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.|Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Lori A
LA
Shutter
Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, 3550 Terrace Street, Pittsburgh, PA, 15261, USA.|Safar Center for Resuscitation Research, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.|Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.|Department of Anesthesiology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Robert S B
RS
Clark
Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, 3550 Terrace Street, Pittsburgh, PA, 15261, USA.|Safar Center for Resuscitation Research, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.|Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.|Department of Anesthesiology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.|Clinical and Translational Science Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Patrick M
PM
Kochanek
Clinical and Translational Science Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.|School of Nursing, University of Pittsburgh, Pittsburgh, PA, USA.|Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA.
Yvette P
YP
Conley
D000293:Adolescent; D000328:Adult; D000368:Aged; D001929:Brain Edema / Q000209:etiology / Q000235:genetics*; D000070642:Brain Injuries, Traumatic / Q000150:complications / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D065840:Protective Factors; D012307:Risk Factors; D012720:Severity of Illness Index; D064233:Sulfonylurea Receptors / Q000235:genetics*; D055815:Young Adult
C577507:ABCC8 protein, human; D064233:Sulfonylurea Receptors
ABCC8; Cerebral edema; Single nucleotide polymorphism (SNP); Sulfonylurea receptor-1 (Sur1); Traumatic brain injury
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