TY - JOUR
T1 - MUC5AC Genetic Variation Is Associated With Tuberculous Meningitis Cerebral Spinal Fluid Cytokine Responses and Mortality
AU - Sabo, Michelle C.
AU - Thuong, Nguyen T. T.
AU - Chang, Xuling
AU - Ardiansyah, Edwin
AU - Tram, Trinh T. B.
AU - Hai, Hoang T.
AU - Nghia, Ho D. T.
AU - Bang, Nguyen D.
AU - Dian, Sofiati
AU - Ganiem, A. Rizal
AU - Shaporifar, Shima
AU - Kumar, Vinod
AU - Li, Zheng
AU - Hibberd, Martin
AU - Khor, Chiea Chuen
AU - Thwaites, Guy E.
AU - Heemskerk, Dorothee
AU - van Laarhoven, Arjan
AU - van Crevel, Reinout
AU - Dunstan, Sarah J.
AU - Shah, Javeed A.
N1 - Funding Information:
Acknowledgments. We thank all the participants in the parent studies used in these analyses. We also acknowledge the clinical, laboratory, and administrative staff at each study site for their dedication and assistance with this project. Finally, we would like to acknowledge the Genotype-Tissue Expression Project (GTEx), which supports the platform on which eQTL analyses were performed. At the time of publication, the GTEx Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by the National Cancer Institute, the National Human Genome Research Institute, the National Heart, Lung, and Blood Institute, the National Institute on Drug Abuse, the National Institute of Mental Health, and the National Institute of Neurological Disorders and Stroke. The data used for the analyses described in this manuscript were obtained from the GTEx Portal eQTL calculator on 30 July 2021.
Funding Information:
Financial support. This work was supported by the National Institute of Child Health and Human Development (grant number K23HD100221 to M. C. S.); the National Institute of Allergy and Infectious Diseases (grant numbers R01 AI136921 to J. A. S., R01 AI145781 to A. v. L., V. K., and R. v. C., and 1P30AI168034-01 to the Seattle TB Research Advancement Center, which supports S. S.); the University of Washington Center for AIDS Research (grant number AI027757 to M. C. S.); the Wellcome Trust (grant numbers 206724/Z/17/Z Intermediate Fellowship in Public Health and Tropical Medicine to N. T. T. T., and 106680/B/14/Z Major Overseas Program Funding to G. T.); and the National Health and Medical Research Council, Australia (grant number APP1056689 to S. J. D.).
Publisher Copyright:
© 2023 The Author(s). Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved.
PY - 2023/8/1
Y1 - 2023/8/1
N2 - 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 tumor necrosis factor (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 IFN-γ(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 =. 02), but not pulmonary tuberculosis (OR, 1.11, 95% CI,. 98-1.25; P =. 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 =. 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 =. 02), and an Indonesia validation cohort (n = 468, 127/287, 44.3% vs 65/181, 35.9%; log-rank P =. 06). Conclusions: MUC5AC variants may contribute to immune changes that influence TBM outcomes.
AB - 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 tumor necrosis factor (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 IFN-γ(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 =. 02), but not pulmonary tuberculosis (OR, 1.11, 95% CI,. 98-1.25; P =. 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 =. 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 =. 02), and an Indonesia validation cohort (n = 468, 127/287, 44.3% vs 65/181, 35.9%; log-rank P =. 06). Conclusions: MUC5AC variants may contribute to immune changes that influence TBM outcomes.
KW - MUC5AC
KW - genetics
KW - mucins
KW - tuberculous meningitis
UR - https://www.scopus.com/pages/publications/85168222220
UR - https://www.ncbi.nlm.nih.gov/pubmed/36823694
UR - https://www.scopus.com/pages/publications/85168222220
U2 - 10.1093/infdis/jiad050
DO - 10.1093/infdis/jiad050
M3 - Article
C2 - 36823694
SN - 0022-1899
VL - 228
SP - 343
EP - 352
JO - Journal of infectious diseases
JF - Journal of infectious diseases
IS - 3
ER -
SDG 3 Good Health and Well-being