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

Rationale Lung mucins are an understudied component of the mucosal immune response and may influence tuberculosis pathogenesis and outcomes. Objectives To assess if variants in lung mucins MUC5B and MUC5AC are associated with Mycobacterium tuberculosis immune responses, susceptibility, and outcomes. Methods We 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 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), 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). Conclusions The MUC5AC rs28737416 T/T and T/C genotypes were associated with higher susceptibility and mortality from TBM and lower CSF concentrations of TNF and IFNγ compared to the C/C genotype, suggesting that MUC5AC contributes to immune changes that influence TBM outcomes. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the National Institute of Child Health and Human Development [1K23HD100221 to MCS] and the National Institute of Allergy and Infectious Diseases [R01 AI136921 to JAS and R01AI145781 to AvL, VK and RvC], both at the National Institutes of Health, the University of Washington Center for AIDS Research [AI027757 to MCS], the Wellcome Trust Intermediate Fellowship in Public Health and Tropical Medicine [206724/Z/17/Z to NTTT], Wellcome Trust Major Overseas Program Funding [106680/B/14/Z to GT], and the National Health and Medical Research Council, Australia (APP1056689 to SJD). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The human subjects review boards of the University of Washington (Seattle, Washington), the Hospital for Tropical Diseases (Ho Chi Minh City, Vietnam), Health Services of Ho Chi Minh City, Hung Vuong Hospital (Ho Chi Minh City, Vietnam), and Pham Ngoc Thach Hospital for Tuberculosis and Lung Diseases (Ho Chi Minh City,Vietnam), gave full approval for this study. The ethics committee of the Ministry of Health, Vietnam, gave full approval for this study. The Oxford Tropical Research Ethics Committee of Oxford University (Oxford, U.K.) gave full approval for this study. The institutional review boards of the Vietnam National Institute of Ophthalmology (Hanoi, Vietnam), Hue University of Medicine and Pharmacy (Danang City, Vietnam), Viet Tiep General Hospital (Hai Phong, Vietnam), Ho Chi Minh City Eye Hospital (Ho Chi Minh City, Vietnam) gave full approval of this study. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are contained in the manuscript