Original Investigation

Human Genetics

, Volume 121, Issue 6, pp 663-673

First online:

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. SteinAffiliated withDepartment of Epidemiology and Biostatistics, Case Western Reserve UniversityTuberculosis Research Unit, Case Western Reserve UniversityCenter for Modern Epidemiology of Infectious Diseases, Case Western Reserve University
  • , Sarah ZalwangoAffiliated withTuberculosis Research Unit, Case Western Reserve UniversityClinical Epidemiology Unit, Makerere University School of Medicine
  • , Allan B. ChiundaAffiliated withDepartment of Epidemiology and Biostatistics, Case Western Reserve UniversityTuberculosis Research Unit, Case Western Reserve University
  • , Christopher MillardAffiliated withDepartment of Epidemiology and Biostatistics, Case Western Reserve University
  • , Dmitry V. LeontievAffiliated withDepartment of Epidemiology and Biostatistics, Case Western Reserve University
  • , Amanda L. HorvathAffiliated withDepartment of Epidemiology and Biostatistics, Case Western Reserve University
  • , Kevin C. CartierAffiliated withDepartment of Epidemiology and Biostatistics, Case Western Reserve University
  • , Keith ChervenakAffiliated withTuberculosis Research Unit, Case Western Reserve University
  • , W. Henry BoomAffiliated withTuberculosis Research Unit, Case Western Reserve University
    • , Robert C. ElstonAffiliated withDepartment of Epidemiology and Biostatistics, Case Western Reserve University
    • , Roy D. MugerwaAffiliated withTuberculosis Research Unit, Case Western Reserve UniversityClinical Epidemiology Unit, Makerere University School of Medicine
    • , Christopher C. WhalenAffiliated withDepartment of Epidemiology and Biostatistics, Case Western Reserve UniversityTuberculosis Research Unit, Case Western Reserve UniversityCenter for Modern Epidemiology of Infectious Diseases, Case Western Reserve University
    • , Sudha K. IyengarAffiliated withDepartment of Epidemiology and Biostatistics, Case Western Reserve University Email author 

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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.