Jha Ruchira M, Puccio Ava M, Okonkwo David O, Zusman Benjamin E, Park Seo-Young, Wallisch Jessica, Empey Philip E, Shutter Lori A, Clark Robert S B, Kochanek Patrick M, Conley Yvette P
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.
Neurocrit Care. 2017 Apr;26(2):213-224. doi: 10.1007/s12028-016-0309-z.
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.
创伤性脑损伤（TBI）中的脑水肿（CE）是多种潜在机制的结果，且与不良预后相关。这些途径中的基因变异性可能解释了在水肿发展过程中观察到的一些临床异质性。磺脲类受体1（Sur1）在CE中的作用得到了支持。然而，之前尚无研究探讨Sur1基因（ABCC8）的基因变异性对CE发展的影响。我们假设ABCC8单核苷酸多态性（SNP）可预测CE。
从385例患者中提取DNA。使用人类核心外显子组v1.2（Illumina）对ABCC8中的SNP进行基因分型。CE测量包括急性CT水肿、平均和峰值颅内压（ICP）以及减压性颅骨切开术的需求。
鉴定出14个次要等位基因频率>0.2的SNP。四个SNP rs2283261、rs3819521、rs2283258和rs1799857与CE测量相关。在多元回归模型中，rs2283261、rs3819521和rs2283258中的纯合子变异基因型发生CT水肿的几率增加（OR 2.45，p = 0.007；OR 2.95，p = 0.025；OR 3.00，p = 0.013），平均ICP更高（β = 3.13，p = 0.000；β = 2.95，p = 0.005；β = 3.20，p = 0.008），峰值ICP也更高（β = 8.00，p = 0.001；β = 7.64，p = 0.007；β = 6.89，p = 0.034）。rs1799857的纯合子野生型基因型进行减压性颅骨切开术的几率降低（OR 0.47，p = 0.004）。
这是第一份评估ABCC8基因变异性对TBI中CE发展影响的报告。ABCC8 SNP的次要等位基因基因型增加了CE的风险，而主要SNP等位基因具有保护作用——这可能暗示了一种进化优势。这些发现可为TBI和其他神经系统疾病中CE的风险分层、治疗反应者以及新型靶向或基于基因的CE治疗方法的开发提供指导。
