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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

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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.

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Acknowledgments

This study would not be possible without the support of the Ugandan National Tuberculosis and Leprosy Control Programme, the generous participation of the Ugandan patients and families, and the medical officers, project coordinators, laboratory personnel and home health visitors who helped collect the epidemiological data. This work is supported in part by the National Institutes of Health, National Center for Research Resources (NCRR) Multidisciplinary Clinical Research Career Development Programs Grant (8K12RR023264), Tuberculosis Research Unit (grant N01-AI95383 from the NIAID), National Institute of General Medical Sciences (GM-28356), a developmental grant from the STERIS Corporation, and the Gene Expression and Genotyping Facility of the Comprehensive Cancer Center of Case Western Reserve University and University Hospitals of Cleveland (P30 CA43703). Some of the results of this paper were obtained by using the program package S.A.G.E., which is supported by a U.S. Public Health Service Resource Grant (RR03655) from the NCRR.

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Authors and Affiliations

  1. Department of Epidemiology and Biostatistics, Case Western Reserve University, Wolstein Research Building Room 1303, 2103 Cornell Rd, Cleveland, OH, 44106, USA

    Catherine M. Stein, Allan B. Chiunda, Christopher Millard, Dmitry V. Leontiev, Amanda L. Horvath, Kevin C. Cartier, Robert C. Elston & Sudha K. Iyengar

  2. Department of Epidemiology and Biostatistics, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA

    Christopher C. Whalen

  3. Tuberculosis Research Unit, Case Western Reserve University, Cleveland, OH, USA

    Catherine M. Stein, Sarah Zalwango, Allan B. Chiunda, Keith Chervenak, W. Henry Boom, Roy D. Mugerwa & Christopher C. Whalen

  4. Center for Modern Epidemiology of Infectious Diseases, Case Western Reserve University, Cleveland, OH, USA

    Catherine M. Stein & Christopher C. Whalen

  5. Clinical Epidemiology Unit, Makerere University School of Medicine, Kampala, Uganda

    Sarah Zalwango & Roy D. Mugerwa

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  1. Catherine M. Stein
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  2. Sarah Zalwango
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  3. Allan B. Chiunda
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  13. Sudha K. Iyengar
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Correspondence to Sudha K. Iyengar.

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C. C. Whalen and S. K. Iyengar contributed equally as senior authors of this work.

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Stein, C.M., Zalwango, S., Chiunda, A.B. et al. 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. Hum Genet 121, 663–673 (2007). https://doi.org/10.1007/s00439-007-0357-8

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