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: 4.82). 08/2007; 121(6):663-73. DOI: 10.1007/s00439-007-0357-8
Source: PubMed


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.

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Available from: Catherine M Stein, Jun 16, 2014
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    • "A modification of this original two-parameter CL model into a one-parameter model was proposed by Goddard et al. (2001). Linkage analysis using the CL model has been proven to be an effective tool for evaluating genetic linkage (Goddard et al., 2001; Arcos-Burgos et al., 2004; Reck et al., 2005; Doan et al., 2006; Rybicki et al., 2007; Stein et al., 2007; Zandi et al., 2007; Song et al., 2011). "
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    ABSTRACT: Olson's conditional-logistic model retains the nice property of the LOD score formulation and has advantages over other methods that make it an appropriate choice for complex trait linkage mapping. However, the asymptotic distribution of the conditional-logistic likelihood-ratio (CL-LR) statistic with genetic constraints on the model parameters is unknown for some analysis models, even in the case of samples comprising only independent sib pairs. We derive approximations to the asymptotic null distributions of the CL-LR statistics and compare them with the empirical null distributions by simulation using independent affected sib pairs. Generally, the empirical null distributions of the CL-LR statistics match well the known or approximated asymptotic distributions for all analysis models considered except for the covariate model with a minimum-adjusted binary covariate. This work will provide useful guidelines for linkage analysis of real data sets for the genetic analysis of complex traits, thereby contributing to the identification of genes for disease traits.
    Frontiers in Genetics 11/2013; 4:244. DOI:10.3389/fgene.2013.00244
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    • "It has been discussed that the selection of controls might partly explain the extensively inconsistency across the genetic association studies on TB susceptibility [10,11]. Recent studies have suggested some genes may actually be related to MTB infection but not TB disease development [38,39], while some other studies have suggested some genes may differentiate between LTBI and active TB disease [40,41]. Such information is important in completely understanding the role of these genes in disease pathogenesis and progression. "
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    ABSTRACT: Association studies have been employed to investigate the relationships between host single nucleotide polymorphisms (SNPs) and susceptibility to pulmonary Tuberculosis (PTB). However, such candidate genetic markers have not been widely studied in Chinese population, especially with respect to the disease development from latent M. tuberculosis infection (LTBI). In this case--control study, 44 candidate SNPs were examined in a total of 600 participants (PTB patients, LTBI controls and healthy controls without M. tuberculosis infection) from Zhengzhou, China. The two groups of controls were frequency matched on gender and age with PTB patients. Genotyping was carried out by the Illumina Golden Gate assay. When comparing PTB patients with LTBI controls but not healthy controls without M. tuberculosis infection, significant associations with disease development were observed for TLR9 1174 A/G, TLR9 1635 A/G and IFNG 2109G/A. The two loci in TLR9 were in LD in our study population (r2=0.96, D'=1.00). A combined effect of the genotypes associated with increased risk of PTB (i.e. TLR9 1174G/G and IFNG 2109 A/A) was found when comparing PTB patients with LTBI controls (p=0.004) but not with healthy controls without infection (p=0.433). Potential associations between TLR9 and IFN-gamma genetic polymorphisms and PTB were observed in a Chinese population which supports further study of the roles played by TLR9/IFN-gamma pathway during the development of PTB.
    BMC Infectious Diseases 10/2013; 13(1):511. DOI:10.1186/1471-2334-13-511 · 2.61 Impact Factor
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    • "Our genetic association studies have taken the approach by Gray- McGuire et al. (2009). We identified the first reported association between TNFR1 gene and TB and also a gene by HIV interaction for this same gene (Stein et al., 2007). Our genome-wide linkage scan (Stein et al., 2008) and subsequent fine mapping studies (Baker et al., 2011) replicated previously a novel set of genes on chromosome 20, CTSZ, and MC3R. "
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    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
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