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

Department of Epidemiology and Biostatistics, Case Western Reserve University, Wolstein Research Building Room 1303, 2103 Cornell Rd, Cleveland, OH 44106, USA.
Human Genetics (Impact Factor: 4.52). 08/2007; 121(6):663-73. DOI: 10.1007/s00439-007-0357-8
Source: PubMed

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-alpha (TNFalpha) in response to culture filtrate as the phenotype. In the present study, we analyzed candidate genes related to TNFalpha regulation and found that interleukin (IL)-10, interferon-gamma receptor 1 (IFNGR1), and TNFalpha receptor 1 (TNFR1) genes were linked and associated to both TB and TNFalpha. 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.

Download full-text


Available from: Catherine M Stein, Jun 16, 2014
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: MOST GENETIC EPIDEMIOLOGICAL STUDY DESIGNS FALL INTO ONE OF TWO CATEGORIES: family based and population-based (case-control). However, recent advances in statistical genetics call for study designs that combine these two approaches. We describe the household contact study design as we have applied it in our several years of study of the epidemiology of tuberculosis. Though we highlight its applicability for genetic epidemiological studies of infectious diseases, there are many facets of this design that are appealing for modern genetic studies, including the simultaneous enrollment of related and unrelated individuals, closely and distantly related individuals, collection of extensive epidemiologic and phenotypic data, and evaluation of effects of shared environment and gene by environment interaction. These study design characteristics are particularly appealing for current sequencing studies.
    Frontiers in Genetics 04/2013; 4:61. DOI:10.3389/fgene.2013.00061
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Several studies have suggested a role for human genetic risk factors in the susceptibility to developing tuberculosis (TB). However, results of these studies have been inconsistent, and one potential reason for these inconsistencies is variation in aspects of study design. Specifically, phenotype definitions and population genetic factors have varied dramatically. Since TB is a complex trait, there are many challenges in designing studies to assess appropriately human genetic risk factors for the development of TB as opposed to the acquisition of latent M. tuberculosis infection. In this review we summarize these important study design differences, with illustrations from the TB genetics literature. We cite specific examples of studies of the NRAMP1 (SLC11A1) gene and present Fisher's combined p values for different stratifications of these studies to further illustrate the impact of study design differences. Finally, we provide suggestions for the design of future genetic epidemiological studies of TB.
    Mammalian Genome 02/2011; 22(1-2):91-9. DOI:10.1007/s00335-010-9301-7 · 2.88 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Africa is the ultimate source of modern humans and as such harbors more genetic variation than any other continent. For this reason, studies of the patterns of genetic variation in African populations are crucial to understanding how genes affect phenotypic variation, including disease predisposition. In addition, the patterns of extant genetic variation in Africa are important for understanding how genetic variation affects infectious diseases that are a major problem in Africa, such as malaria, tuberculosis, schistosomiasis, and HIV/AIDS. Therefore, elucidating the role that genetic susceptibility to infectious diseases plays is critical to improving the health of people in Africa. It is also of note that recent and ongoing social and cultural changes in sub-Saharan Africa have increased the prevalence of non-communicable diseases that will also require genetic analyses to improve disease prevention and treatment. In this review we give special attention to many of the past and ongoing studies, emphasizing those in Sub-Saharan Africans that address the role of genetic variation in human disease.
    Human Genetics 10/2008; 124(2):195. DOI:10.1007/s00439-008-0534-4 · 4.52 Impact Factor