Interaction between host genes and Mycobacterium tuberculosis lineage can affect tuberculosis severity: Evidence for coevolution?

Autoři: Michael L. McHenry aff001;  Jacquelaine Bartlett aff001;  Robert P. Igo, Jr aff001;  Eddie M. Wampande aff002;  Penelope Benchek aff001;  Harriet Mayanja-Kizza aff003;  Kyle Fluegge aff001;  Noemi B. Hall aff001;  Sebastien Gagneux aff004;  Sarah A. Tishkoff aff006;  Christian Wejse aff007;  Giorgio Sirugo aff009;  W. Henry Boom aff010;  Moses Joloba aff002;  Scott M. Williams aff001;  Catherine M. Stein aff001
Působiště autorů: Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America aff001;  Department of Medical Microbiology, College of Health Sciences, Makerere University, Kampala, Uganda aff002;  Department of Medicine and Mulago Hospital, School of Medicine, Makerere University, Kampala, Uganda aff003;  Swiss Tropical and Public Health Institute, Basel, Switzerland aff004;  University of Basel, Basel, Switzerland aff005;  Departments of Genetics and Biology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America aff006;  Department of Infectious Diseases and Center for Global Health, Aarhus University, Aarhus, Denmark aff007;  Bandim Health Project, INDEPTH Network, Bissau, Guinea Bissau aff008;  Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, Unites States of America aff009;  Tuberculosis Research Unit, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America aff010;  Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America aff011
Vyšlo v časopise: Interaction between host genes and Mycobacterium tuberculosis lineage can affect tuberculosis severity: Evidence for coevolution?. PLoS Genet 16(4): e32767. doi:10.1371/journal.pgen.1008728
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008728


Genetic studies of both the human host and Mycobacterium tuberculosis (MTB) demonstrate independent association with tuberculosis (TB) risk. However, neither explains a large portion of disease risk or severity. Based on studies in other infectious diseases and animal models of TB, we hypothesized that the genomes of the two interact to modulate risk of developing active TB or increasing the severity of disease, when present. We examined this hypothesis in our TB household contact study in Kampala, Uganda, in which there were 3 MTB lineages of which L4-Ugandan (L4.6) is the most recent. TB severity, measured using the Bandim TBscore, was modeled as a function of host SNP genotype, MTB lineage, and their interaction, within two independent cohorts of TB cases, N = 113 and 121. No association was found between lineage and severity, but association between multiple polymorphisms in IL12B and TBscore was replicated in two independent cohorts (most significant rs3212227, combined p = 0.0006), supporting previous associations of IL12B with TB susceptibility. We also observed significant interaction between a single nucleotide polymorphism (SNP) in SLC11A1 and the L4-Ugandan lineage in both cohorts (rs17235409, meta p = 0.0002). Interestingly, the presence of the L4-Uganda lineage in the presence of the ancestral human allele associated with more severe disease. These findings demonstrate that IL12B is associated with severity of TB in addition to susceptibility, and that the association between TB severity and human genetics can be due to an interaction between genes in the two species, consistent with host-pathogen coevolution in TB.

Klíčová slova:

HIV – Host-pathogen interactions – Human genetics – Molecular genetics – Mycobacterium tuberculosis – Tuberculosis – Variant genotypes – Coevolution


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