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

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

  • Michael L. McHenry, Case Western Reserve University
  • ,
  • Jacquelaine Bartlett, Case Western Reserve University
  • ,
  • Robert P. Igo, Case Western Reserve University
  • ,
  • Eddie M. Wampande, Makerere University
  • ,
  • Penelope Benchek, Case Western Reserve University
  • ,
  • Harriet Mayanja-Kizza, Makerere University
  • ,
  • Kyle Fluegge, Case Western Reserve University
  • ,
  • Noemi B. Hall, Case Western Reserve University
  • ,
  • Sebastien Gagneux, Swiss Tropical and Public Health Institute (Swiss TPH), University of Basel
  • ,
  • Sarah A. Tishkoff, University of Pennsylvania
  • ,
  • Christian Wejse
  • Giorgio Sirugo, University of Pennsylvania
  • ,
  • W. Henry Boom, Case Western Reserve University
  • ,
  • Moses Joloba, Makerere University
  • ,
  • Scott M. Williams, Case Western Reserve University
  • ,
  • Catherine M. Stein, Case Western Reserve University

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.

OriginalsprogEngelsk
Artikelnummere1008728
TidsskriftPLOS Genetics
Vol/bind16
Nummer4
ISSN1553-7390
DOI
StatusUdgivet - apr. 2020

Se relationer på Aarhus Universitet Citationsformater

ID: 187088737