Human Genetics

, Volume 121, Issue 6, pp 663–673

Linkage and association analysis of candidate genes for TB and TNFα cytokine expression: evidence for association with IFNGR1, IL-10, and TNF receptor 1 genes

  • Catherine M. Stein
  • Sarah Zalwango
  • Allan B. Chiunda
  • Christopher Millard
  • Dmitry V. Leontiev
  • Amanda L. Horvath
  • Kevin C. Cartier
  • Keith Chervenak
  • W. Henry Boom
  • Robert C. Elston
  • Roy D. Mugerwa
  • Christopher C. Whalen
  • Sudha K. Iyengar
Original Investigation

Abstract

Tuberculosis (TB) is a growing public health threat globally and several studies suggest a role of host genetic susceptibility in increased TB risk. As part of a household contact study in Kampala, Uganda, we have taken a unique approach to the study of genetic susceptibility to TB by developing an intermediate phenotype model for TB susceptibility, analyzing levels of tumor necrosis factor-α (TNFα) in response to culture filtrate as the phenotype. In the present study, we analyzed candidate genes related to TNFα regulation and found that interleukin (IL)-10, interferon-gamma receptor 1 (IFNGR1), and TNFα receptor 1 (TNFR1) genes were linked and associated to both TB and TNFα. We also show that these associations are with progression to active disease and not susceptibility to latent infection. This is the first report of an association between TB and TNFR1 in a human population and our findings for IL-10 and IFNGR1 replicate previous findings. By observing pleiotropic effects on both phenotypes, we show construct validity of our intermediate phenotype model, which enables the characterization of the role of these genetic polymorphisms on TB pathogenesis. This study further illustrates the utility of such a model for disentangling complex traits.

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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Catherine M. Stein
    • 1
    • 3
    • 4
  • Sarah Zalwango
    • 3
    • 5
  • Allan B. Chiunda
    • 1
    • 3
  • Christopher Millard
    • 1
  • Dmitry V. Leontiev
    • 1
  • Amanda L. Horvath
    • 1
  • Kevin C. Cartier
    • 1
  • Keith Chervenak
    • 3
  • W. Henry Boom
    • 3
  • Robert C. Elston
    • 1
  • Roy D. Mugerwa
    • 3
    • 5
  • Christopher C. Whalen
    • 2
    • 3
    • 4
  • Sudha K. Iyengar
    • 1
  1. 1.Department of Epidemiology and BiostatisticsCase Western Reserve UniversityClevelandUSA
  2. 2.Department of Epidemiology and BiostatisticsCase Western Reserve UniversityClevelandUSA
  3. 3.Tuberculosis Research UnitCase Western Reserve UniversityClevelandUSA
  4. 4.Center for Modern Epidemiology of Infectious DiseasesCase Western Reserve UniversityClevelandUSA
  5. 5.Clinical Epidemiology UnitMakerere University School of MedicineKampalaUganda

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