Accumulating evidence shows that the extent of brain injury and the clinical outcome after traumatic brain injury (TBI) are modulated to some degree by genetic variants. tested for associations with 6-month GOS after adjusting for age GCS score and sex. Significant associations with TBI outcome were detected for rs3763043 (OR [95% confidence interval (CI)]: 5.15 [1.60-16.5] value significance level assuming the Bonferroni correction for multiple comparisons was set at 0.05/6=0.008. Power analysis showed that the sample size Org 27569 was sufficient to detect an OR of 1 1.67-2.15 with a statistical power of >80% assuming a significance level of 0.05 the additive mode of inheritance and a minor allele frequency of 37.3% and 8.4% (the highest (in rs4800773) and the lowest (in rs11661256) in the sample. respectively). Table 4. Allelic and Genotype Frequencies for Single Nucleotide Polymorphisms in the Traumatic Brain Injury Sample and Those with Favorable or Unfavorable Outcome Univariate and multivariate single locus analysis with 6 months GOS outcome is presented in Table 5. In multivariate analysis age (OR:1.09 95 CI [1.06-1.12] p<0.001) and GCS score at admission (OR: 0.56 95 CI [0.48-0.65] p<0.001) but not sex were significantly associated with GOS at 6 months. In addition two tag SNPs were found to influence the outcome of TBI: rs3763043 and rs3875089. In the rs3763043 SNP the TT genotype was significantly more prevalent in the poor outcome group of patients yielding an OR of 5.15 (95% CI [1.60-16.5] p=0.006) in the recessive model. The dominant and allele difference models also revealed significant associations with TBI outcome that survived the Bonferroni correction. In the rs3875089 SNP the less common C allele was found to have a protective effect because it was more frequent among the patients with favorable outcome. Both dominant model and Org 27569 allele difference showed strong associations (OR: 0.22 95 CI [0.07-0.65] p=0.006 and OR:0.18 95 CI [0.07-0.50] p=0.0009 respectively) that remained significant after adjustment for multiple comparisons. Table 5. Univariate and Multivariate Single Locus Association with 6 months Glasgow Outcome Score outcome after Traumatic Brain Injury Pairwise LD between the studied AQP4 tag SNPs in the TBI sample (Supplementary Fig. 2; see online supplementary material at ftp.liebertpub.com) has revealed high disequilibrium (D’) values between most tag SNPs across the AQP4 gene. In the haplotype multilocus-based analysis of the tag SNPs (Table 6) six common haplotypes were predicted to be formed from the six tag SNPs (predicted frequency >0.05; Table 4). The ATTAGT common haplotype was predicted to be significantly overrepresented in the poor outcome group compared with the favorable outcome group (16.9% vs. 7.4% OR: 2.94 95 CI [1.34-6.36] p=0.0065). This haplotype combines the T allele of rs3763043 and the T allele of rs3875089 that were associated with poor outcome in the single locus analysis. Table 6. Predicted Haplotypes from the AQP4 TAG Single Nucleotide Polymorphisms in Good and Poor Outcome Traumatic Brain Injury Groups Univariate and multivariate single locus analyses with initial TBI severity and the presence of intracranial hemorrhage are presented in Supplementary Tables 1 and 2 (see online supplementary material at ftp.liebertpub.com). These analyses did not provide any Rabbit polyclonal to AHCY. significant effect of AQP4 SNPs except for a marginal association of rs4800773 with hemorrhagic events (p=0.04) which however did not survive Bonferroni correction. Discussion In the present study specific variants of the AQP4 gene which codes for the predominant water channel in the central nervous system were found to significantly influence the 6-month clinical outcome after TBI. No similar effects were found with respect to the initial TBI severity as measured Org 27569 by the GCS score at admission or the presence of intracranial hemorrhage. It is known that the ongoing sequelae of Org 27569 damage to nervous tissue after the initial TBI is perpetuated by cerebral edema increased intracranial pressure tissue hypoxia-ischemia and disruption of the blood-brain barrier (BBB)2. There are two major types of brain edema: cytotoxic and vasogenic.23 Cytotoxic edema occurs when brain cells are damaged and the Na-K ATPase Org 27569 fails to maintain transmembrane ion gradients while the BBB.

Accumulating evidence shows that the extent of brain injury and the

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