Leukotriene A4 Hydrolase Genotype and HIV Infection Influence Intracerebral Inflammation and Survival From Tuberculous Meningitis.

BACKGROUND: Tuberculous meningitis (TBM) is the most devastating form of tuberculosis, yet very little is known about the pathophysiology. We hypothesized that the genotype of leukotriene A4 hydrolase (encoded by LTA4H), which determines inflammatory eicosanoid expression, influences intracerebral inflammation, and predicts survival from TBM. METHODS: We characterized the pretreatment clinical and intracerebral inflammatory phenotype and 9-month survival of 764 adults with TBM. All were genotyped for single-nucleotide polymorphism rs17525495, and inflammatory phenotype was defined by cerebrospinal fluid (CSF) leukocyte and cytokine concentrations. RESULTS: LTA4H genotype predicted survival of human immunodeficiency virus (HIV)-uninfected patients, with TT-genotype patients significantly more likely to survive TBM than CC-genotype patients, according to Cox regression analysis (univariate P = .040 and multivariable P = .037). HIV-uninfected, TT-genotype patients had high CSF proinflammatory cytokine concentrations, with intermediate and lower concentrations in those with CT and CC genotypes. Increased CSF cytokine concentrations correlated with more-severe disease, but patients with low CSF leukocytes and cytokine concentrations were more likely to die from TBM. HIV infection independently predicted death due to TBM (hazard ratio, 3.94; 95% confidence interval, 2.79-5.56) and was associated with globally increased CSF cytokine concentrations, independent of LTA4H genotype. CONCLUSIONS: LTA4H genotype and HIV infection influence pretreatment inflammatory phenotype and survival from TBM. LTA4H genotype may predict adjunctive corticosteroid responsiveness in HIV-uninfected individuals

MUC5AC genetic variation is associated with tuberculous meningitis CSF cytokine responses and mortality

BACKGROUND: The purpose of this study was to assess if single nucleotide polymorphisms (SNPs) in lung mucins MUC5B and MUC5AC are associated with Mycobacterium tuberculosis outcomes. METHODS: Independent SNPs in MUC5B and MUC5AC (genotyped by Illumina HumanOmniExpress array) were assessed for associations with TNF concentrations (measured by immunoassay) in cerebral spinal fluid (CSF) from tuberculous meningitis (TBM) patients. SNPs associated with CSF TNF concentrations were carried forward for analyses of pulmonary and meningeal tuberculosis susceptibility and TBM mortality. RESULTS: MUC5AC SNP rs28737416 T allele was associated with lower CSF concentrations of TNF(p = 1.8*10-8) and IFNγ(p = 2.3*10-6). In an additive genetic model, rs28737416 T/T genotype was associated with higher susceptibility to TBM (odds ratio [OR] 1.24, 95% confidence interval [CI] 1.03, 1.49; p = 0.02), but not pulmonary tuberculosis (OR 1.11, 95% CI 0.98, 1.25; p = 0.10). TBM mortality was higher among participants with the rs28737416 T/T and T/C genotypes (35/119, 30.4%) versus the C/C genotype (11/89, 12.4%; log-rank p = 0.005) in a Vietnam discovery cohort (N = 210), an independent Vietnam validation cohort (N = 87; 9/87, 19.1% vs 1/20, 2.5%; log-rank p = 0.02), and an Indonesia validation cohort (N = 468, 127/287, 44.3% vs 65/181, 35.9%, log-rank p = 0.06). CONCLUSIONS: MUC5AC variants may contribute to immune changes that influence TBM outcomes