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Interaction between host genes and M. tuberculosis lineage can affect tuberculosis severity: evidence for co-evolution

Interaction between host genes and M. tuberculosis lineage can affect tuberculosis severity: evidence for co-evolution

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dc.contributor.author Michael L. McHenry
dc.contributor.author Jacquelaine Bartlett
dc.contributor.author Robert P. Igo
dc.contributor.author Eddie M. Wampande
dc.contributor.author Penelope Bencheck
dc.contributor.author Harriet Mayanja-Kizza
dc.contributor.author Kyle Fluegge
dc.contributor.author Noemi B. Hall
dc.contributor.author S. Gagneux
dc.contributor.author Sarah A. Tishkoff
dc.contributor.author Christian Wejse
dc.contributor.author Giorgio Sirugo
dc.contributor.author W. H. Boom
dc.contributor.author Moses Joloba
dc.contributor.author Scott M. Williams
dc.contributor.author Catherine M. Stein
dc.date.accessioned 2021-01-11T13:51:41Z
dc.date.available 2021-01-11T13:51:41Z
dc.date.issued 2019
dc.identifier.uri https://combine.alvar.ug/handle/1/49441
dc.description.abstract Abstract 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 122. 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, providing evidence of host-pathogen coevolution in TB. AUTHOR SUMMARY Susceptibility to tuberculosis (TB) is affected by genetic variation in both the human host and the causative bacterium, Mycobacterium tuberculosis. However, prior studies of the genetics of each species have not explained a large part of TB risk. The possibility exists that risk can be better estimated from patterns of variation in two species as a unit, such that some combinations provide increased risk, or in the presence of TB, increased disease severity. We hypothesized that alleles in the two species that have co-existed for long periods are more likely to reduce disease severity so as to promote prolonged co-occurrence. We tested this by studying TB severity in two patient cohorts from Uganda for which paired MTB-human DNA were available. We examined severity, as measured by the Bandim TBscore, and assessed whether there was an interaction between MTB lineage and SNPs in the host with this metric. Our results indicate that the most recent TB lineage (L4.6/Uganda) when found together with an ancestral allele in SLC11A1 resulted in more severe disease. This finding is consistent with the conclusion that MTB and human have coevolved to modulate TB severity.
dc.publisher Cold Spring Harbor Laboratory
dc.title Interaction between host genes and M. tuberculosis lineage can affect tuberculosis severity: evidence for co-evolution
dc.type Preprint
dc.identifier.doi 10.1101/769448
dc.identifier.mag 2972840705
dc.identifier.lens 018-444-825-995-059
dc.identifier.spage 769448
dc.subject.lens-fields Genotype
dc.subject.lens-fields SNP
dc.subject.lens-fields Single-nucleotide polymorphism
dc.subject.lens-fields Allele
dc.subject.lens-fields Immunology
dc.subject.lens-fields Mycobacterium tuberculosis
dc.subject.lens-fields Disease
dc.subject.lens-fields Tuberculosis
dc.subject.lens-fields Genetic variation
dc.subject.lens-fields Biology


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