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Gene-gene interaction between tuberculosis candidate genes in a South African population

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Abstract

In a complex disease such as tuberculosis (TB) it is increasingly evident that gene-gene interactions play a far more important role in an individual’s susceptibility to develop the disease than single polymorphisms on their own, as one gene can enhance or hinder the expression of another gene. Gene-gene interaction analysis is a new approach to elucidate susceptibility to TB. The possibility of gene-gene interactions was assessed, focusing on 11 polymorphisms in nine genes (DC-SIGN, IFN-γ, IFNGR1, IL-8, IL-1Ra, MBL, NRAMP1, RANTES, and SP-D) that have been associated with TB, some repeatedly. An optimal model, which best describes and predicts TB case–control status, was constructed. Significant interactions were detected between eight pairs of variants. The models fitted the observed data extremely well, with p < 0.0001 for all eight models. A highly significant interaction was detected between INFGR1 and NRAMP1, which is not surprising because macrophage activation is greatly enhanced by IFN-γ and IFN-γ response elements that are present in the human NRAMP1 promoter region, providing further evidence for their interaction. This study enabled us to test the theory that disease outcome may be due to interaction of several gene effects. With eight instances of statistically significant gene-gene interactions, the importance of epistasis is clearly identifiable in this study. Methods for studying gene-gene interactions are based on a multilocus and multigene approach, consistent with the nature of complex-trait diseases, and may provide the paradigm for future genetic studies of TB.

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Acknowledgments

We thank all the participants in this study.

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The authors have no conflicts of interest or financial ties to disclose.

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Authors and Affiliations

  1. Molecular Biology and Human Genetics, MRC Centre for Molecular and Cellular Biology and the DST/NRF Centre of Excellence for Biomedical TB Research, Faculty of Health Sciences, Stellenbosch University, PO Box 19063, Tygerberg, 7505, South Africa

    Erika de Wit, Paul D. van Helden & Eileen G. Hoal

  2. Biostatistics Unit, Medical Research Council, Tygerberg, South Africa

    Lize van der Merwe

  3. Department of Statistics, University of Western Cape, Bellville, South Africa

    Lize van der Merwe

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  1. Erika de Wit
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  2. Lize van der Merwe
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  3. Paul D. van Helden
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  4. Eileen G. Hoal
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Correspondence to Eileen G. Hoal.

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de Wit, E., van der Merwe, L., van Helden, P.D. et al. Gene-gene interaction between tuberculosis candidate genes in a South African population. Mamm Genome 22, 100–110 (2011). https://doi.org/10.1007/s00335-010-9280-8

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