PROMOTER POLYMORPHISMS OF THE PRO-INFLAMMATORY CYTOKINE GENES IL-6 (-174 G/C, RS1800795) AND TNF-Α (-308 G/A, RS1800629) AND THE RISK OF INFECTIOUS-INFLAMMATORY COMPLICATIONS IN TRAUMATIC BRAIN INJURY

Abstract

Background and aim. Clinical outcomes after traumatic brain injury (TBI) vary widely among patients with comparable injury severity, partly because of inter-individual differences in the systemic inflammatory response. Interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) are central drivers of post-traumatic neuroinflammation, and functional promoter polymorphisms IL-6 -174 G/C (rs1800795) and TNF-α -308 G/A (rs1800629) modulate their expression. We aimed to determine the genotype and allele distributions of these two variants in patients with TBI, to relate them to circulating C-reactive protein (CRP) as a downstream inflammatory read-out, and to evaluate their association with infectious-inflammatory complications and 6-month functional outcome.Methods. Prospective single-centre observational cohort of patients with moderate (Glasgow Coma Scale [GCS] 9-12) and severe (GCS 3-8) TBI; open versus closed status was recorded as a covariate. IL-6 rs1800795 and TNF-α rs1800629 were genotyped and tested for Hardy-Weinberg equilibrium (HWE). Serum CRP was measured serially and the peak value was used. Infectious-inflammatory complications (nosocomial pneumonia, meningitis or ventriculitis, sepsis) were defined by standard criteria; outcome was assessed with the Extended Glasgow Outcome Scale (GOS-E) at discharge and at 6 months. Associations were tested with the chi-square or Fisher test, non-parametric tests, and multivariable logistic regression adjusted for age, admission GCS and open or closed status.Results. In this preliminary interim analysis (112 patients, 120 controls), the high-expression TNF-α -308 A allele was associated with higher peak CRP and a higher incidence of infectious-inflammatory complications (adjusted OR 3.4, 95% CI 1.3 to 8.9), while the IL-6 -174 CC genotype showed a lower complication rate. Admission GCS and the combined high-risk cytokine genotype were independent predictors in a multivariable model (area under the ROC curve 0.78).Conclusion. Promoter polymorphisms of IL-6 and TNF-α, integrated through a CRP-based inflammatory read-out, are candidate molecular markers for stratifying the risk of infectious-inflammatory complications after TBI. Adequately powered, multicentre confirmation is required.