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

Authors

  • Catherine M. Stein
    • Department of Epidemiology and BiostatisticsCase Western Reserve University
    • Tuberculosis Research UnitCase Western Reserve University
    • Center for Modern Epidemiology of Infectious DiseasesCase Western Reserve University
  • Sarah Zalwango
    • Tuberculosis Research UnitCase Western Reserve University
    • Clinical Epidemiology UnitMakerere University School of Medicine
  • Allan B. Chiunda
    • Department of Epidemiology and BiostatisticsCase Western Reserve University
    • Tuberculosis Research UnitCase Western Reserve University
  • Christopher Millard
    • Department of Epidemiology and BiostatisticsCase Western Reserve University
  • Dmitry V. Leontiev
    • Department of Epidemiology and BiostatisticsCase Western Reserve University
  • Amanda L. Horvath
    • Department of Epidemiology and BiostatisticsCase Western Reserve University
  • Kevin C. Cartier
    • Department of Epidemiology and BiostatisticsCase Western Reserve University
  • Keith Chervenak
    • Tuberculosis Research UnitCase Western Reserve University
  • W. Henry Boom
    • Tuberculosis Research UnitCase Western Reserve University
  • Robert C. Elston
    • Department of Epidemiology and BiostatisticsCase Western Reserve University
  • Roy D. Mugerwa
    • Tuberculosis Research UnitCase Western Reserve University
    • Clinical Epidemiology UnitMakerere University School of Medicine
  • Christopher C. Whalen
    • Department of Epidemiology and BiostatisticsCase Western Reserve University
    • Tuberculosis Research UnitCase Western Reserve University
    • Center for Modern Epidemiology of Infectious DiseasesCase Western Reserve University
    • Department of Epidemiology and BiostatisticsCase Western Reserve University
Original Investigation

DOI: 10.1007/s00439-007-0357-8

Cite this article as:
Stein, C.M., Zalwango, S., Chiunda, A.B. et al. Hum Genet (2007) 121: 663. doi:10.1007/s00439-007-0357-8

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.

Copyright information

© Springer-Verlag 2007