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

RationaleLung mucins are an understudied component of the mucosal immune response and may influence tuberculosis pathogenesis and outcomes. ObjectivesTo assess if variants in lung mucins MUC5B and MUC5AC are associated with Mycobacterium tuberculosis immune responses, susceptibility, and outcomes. MethodsWe characterized four haplotype tagging single nucleotide polymorphisms (SNPs) in MUC5B and MUC5AC for association with log2 TNF concentrations in cerebral spinal fluid (CSF) from TBM patients. SNPs associated with CSF TNF concentrations were carried forward for analyses of pulmonary and meningeal TB susceptibility and TBM mortality. Measurements and Main ResultsMUC5AC SNP rs28737416 T allele was associated with lower CSF concentrations of TNF(p=1.8*10-8) and IFN{gamma}(p=2.3*10-6), and higher TBM, but not pulmonary TB, susceptibility (OR 1.24, 95% confidence interval 1.03, 1.49; p=0.021). Mortality from TBM was higher among participants with the rs28737416 T/T and T/C genotype (35/119, 30.4%) versus the C/C genotype (11/89, 12.4%; log-rank p=0.005) in a Vietnamese cohort (N=211). This finding was confirmed in an independent Vietnamese validation cohort (N=87; 9/87, 19.1% vs 1/20, 2.5%; log-rank p=0.02) and an Indonesian validation cohort (N=468, 127/287, 44.3% vs 65/181, 35.9%, log-rank p=0.06). ConclusionsThe MUC5AC rs28737416 T/T and T/C genotypes were associated with higher susceptibility and mortality from TBM and lower CSF concentrations of TNF and IFN{gamma} compared to the C/C genotype, suggesting that MUC5AC contributes to immune changes that influence TBM outcomes.