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.
KeywordsABCC8 Cerebral edema Traumatic brain injury Single nucleotide polymorphism (SNP) Sulfonylurea receptor-1 (Sur1)
- 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
- 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. https://clinicaltrials.gov/ct2/show/NCT01132703?term=glibenclamide+traumatic+brain+injury&rank=2.
- 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.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
- 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