Safar Center for Resuscitation Research and Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
J Neurotrauma. 2010 Mar;27(3):465-71. doi: 10.1089/neu.2009.1171.
Poly(ADP-ribose) polymerase-1 (PARP-1) plays an important role in the cellular response to stress and DNA damage. However, excessive activity of PARP-1 exacerbates brain injury via NAD+ depletion and energy failure. The purpose of this study was to determine if tagging single nucleotide polymorphisms (tSNPs) covering multiple regions of the PARP-1 gene are related to outcome after traumatic brain injury (TBI) in humans. DNA from 191 adult patients with severe TBI was assayed for four tSNPs corresponding to haplotype blocks spanning the PARP-1 gene. Categorization as favorable or poor outcome was based on Glasgow Outcome Scale (GOS) score assigned at 6 months. PARP-1 enzyme activity was indirectly evaluated by quantifying poly-ADP-ribose (PAR)-modified proteins in cerebrospinal fluid (CSF) using an enzyme-linked immunosorbent assay. In multiple logistic regression analysis controlling for age, initial Glasgow Coma Scale score, and gender, the AA genotype of SNP rs3219119 was an independent predictor of favorable neurologic outcome. This SNP tags a haplotype block spanning the automodification and catalytic domains of the PARP-1 gene. SNP rs2271347 correlated with CSF PAR-modified protein level. This SNP, which did not correlate with outcome, tags a haplotype block spanning the promoter region of the PARP-1 gene. We conclude that after severe TBI in humans, a PARP-1 polymorphism within the automodification-catalytic domain is associated with neurological outcome, while a polymorphism within the promoter region was associated with CSF PAR-modified protein level. These findings must be replicated in a prospective study before the relevance of PARP-1 polymorphisms after TBI can be established.
聚（ADP-核糖）聚合酶-1（PARP-1）在细胞对压力和 DNA 损伤的反应中起着重要作用。然而，PARP-1 的过度活性通过 NAD+耗竭和能量衰竭加剧脑损伤。本研究旨在确定覆盖 PARP-1 基因多个区域的单核苷酸多态性（tSNP）是否与人类创伤性脑损伤（TBI）后的结果相关。对 191 名成年严重 TBI 患者的 DNA 进行了四种 tSNP 的检测，这些 tSNP 对应横跨 PARP-1 基因的单体型块。根据 6 个月时分配的格拉斯哥结局量表（GOS）评分，将分类为良好或不良结局。通过酶联免疫吸附试验间接评估 PARP-1 酶活性，定量脑脊液（CSF）中多聚 ADP-核糖（PAR）修饰蛋白。在多变量逻辑回归分析中，控制年龄、初始格拉斯哥昏迷量表评分和性别，SNP rs3219119 的 AA 基因型是良好神经结局的独立预测因子。该 SNP 标记横跨 PARP-1 基因自动修饰和催化结构域的单体型块。SNP rs2271347 与 CSF PAR 修饰蛋白水平相关。该 SNP 与结局不相关，标记横跨 PARP-1 基因启动子区域的单体型块。我们的结论是，在人类严重 TBI 后，PARP-1 基因自动修饰-催化结构域内的多态性与神经结局相关，而启动子区域内的多态性与 CSF PAR 修饰蛋白水平相关。在 TBI 后 PARP-1 多态性的相关性得到前瞻性研究证实之前，必须在其他研究中重复这些发现。
