Association between cytokine gene polymorphisms and clinical outcome after traumatic brain injury

Abstract

DNA from buccal swabs has previously been collected from two separate cohorts totally 1463 patients treated after TBI. A clinical database for these patients has been collated, including details of their injuries, outcome (GOS) after 6 months (n=1067, identified prospectively) or outcome 15-25 years after injury (n=396, identified retrospectively). Eleven single nucleotide polymorphisms (SNPs) in five cytokine genes were identified from the literature as having potential influence on outcome after TBI; -238 and -308 in TNFA, -174, -572 and -597 in IL-6, -889 in IL-1A, -31,-511 & +3953 in IL-1B and -509 and -800 in TGFB. After assessment of the DNA samples a DNA pre-amplification technique (GenomiPhi, Amersham Biosciences) was identified to enable multiple SNPtyping assays to be performed on a limited DNA resource.

In the prospective cohort (n=1067) the TNFA -308 SNP was associated with outcome 6-months after TBI (p=0.009), with the rarer A allele associated with a poorer outcome. None of the other SNPs demonstrated an association with 6-month outcome when considered individually. Patients who had composites of the TNFA -308, IL1A -889 and IL1B +3953 SNPtypes were prone to poorer outcome. The TNFA GA haplotype was also associated with 6-month outcome (p=0.036). The IL1A -889 SNP was associated with the occurrence of seizures (p=0.049) and raised intracranial pressure (p=0.01) after TBI, whilst the IL1B-31 SNP was associated with severe infections (p=0.027).

In the retrospective cohort (n=396) the TNFA -308 SNP (p=0.018) and the GA haplotype (p=0.021) were also found to be associated with ‘long term’ outcome. Two SNPs (IL1A -889 and IL1B +3953) and a haplotype (TTCT) in the IL-1 gene cluster were associated with a change in functional ability (as assessed by the GOS) between 6-month and ‘long-term’ assessments. When possessed together the rarer alleles at TNFA -308 and IL1A -889 significantly increased the risk of a decline in function (p=0.03).

Organotypic hippocampal slice cultures (OHSCs) were used to investigate the potential neurotoxic or neuroprotective effects of IL-6 and apolipoprotein E in parallel in-vitro studies, in order to explore underlying mechanisms. IL-6 exerted a protective effect in an OHSC model of ischemia but not in an excitotoxicity model. In the same models significantly less damage was sustained by cultures treated with apolipoprotein E3 as compared to those with E4 (p=0.04, ischaemia; p=0.003, excitotoxicity).

An association between cytokine gene SNPs and outcome after TBI has been demonstrated. This suggests that neuroinflammation after TBI does have an impact on clinical outcome and TNFα plays a crucial role in the process. These findings will require validation in other cohorts and the true biological effect of the SNPs must be confirmed.

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