Browsing by Author "Elston, Robert C."

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    Genome Scan of M. tuberculosis Infection and Disease in Ugandans
    (PLoS ONE, 2018) Stein, Catherine M.; Zalwango, Sarah; Malone, LaShaunda L.; Won1, Sungho; Mayanja- Kizza, Harriet; Mugerwa, Roy D.; Leontiev, Dmitry V.; Thompson, Cheryl L.; Cartier, Kevin C.; Elston, Robert C.; Iyengar, Sudha K.; Boom, Henry; Whalen, Christopher C.
    Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is an enduring public health problem globally, particularly in sub-Saharan Africa. Several studies have suggested a role for host genetic susceptibility in increased risk for TB but results across studies have been equivocal. As part of a household contact study of Mtb infection and disease in Kampala, Uganda, we have taken a unique approach to the study of genetic susceptibility to TB, by studying three phenotypes. First, we analyzed culture confirmed TB disease compared to latent Mtb infection (LTBI) or lack of Mtb infection. Second, we analyzed resistance to Mtb infection in the face of continuous exposure, defined by a persistently negative tuberculin skin test (PTST-); this outcome was contrasted to LTBI. Third, we analyzed an intermediate phenotype, tumor necrosis factor-alpha (TNFa) expression in response to soluble Mtb ligands enriched with molecules secreted from Mtb (culture filtrate). We conducted a full microsatellite genome scan, using genotypes generated by the Center for Medical Genetics at Marshfield. Multipoint model-free linkage analysis was conducted using an extension of the Haseman-Elston regression model that includes half sibling pairs, and HIV status was included as a covariate in the model. The analysis included 803 individuals from 193 pedigrees, comprising 258 full sibling pairs and 175 half sibling pairs. Suggestive linkage (p,1023) was observed on chromosomes 2q21-2q24 and 5p13-5q22 for PTST-, and on chromosome 7p22-7p21 for TB; these findings for PTST- are novel and the chromosome 7 region contains the IL6 gene. In addition, we replicated recent linkage findings on chromosome 20q13 for TB (p = 0.002). We also observed linkage at the nominal a = 0.05 threshold to a number of promising candidate genes, SLC11A1 (PTST- p = 0.02), IL-1 complex (TB p = 0.01), IL12BR2 (TNFa p = 0.006), IL12A (TB p = 0.02) and IFNGR2 (TNFa p = 0.002). These results confirm not only that genetic factors influence the interaction between humans and Mtb but more importantly that they differ according to the outcome of that interaction: exposure but no infection, infection without progression to disease, or progression of infection to disease. Many of the genetic factors for each of these stages are part of the innate immune system.
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    Heritability Analysis of Cytokines as Intermediate Phenotypes of Tuberculosis
    (The Journal of infectious diseases, 2003) Stein, Catherine M.; Guwatudde, David; Nakakeeto, Margaret; Peters, Pierre; Elston, Robert C.; Tiwari, Hemant K.; Mugerwa, Roy; Whalen, Christopher C.
    Numerous studies have provided support for genetic susceptibility to tuberculosis (TB); however, heterogeneity in disease expression has hampered previous genetic studies. The purpose of this work was to investigate possible intermediate phenotypes for TB. A set of cytokine profiles, including antigen-stimulated whole-blood assays for interferon (IFN)–g, tumor necrosis factor (TNF)–a, transforming growth factor (TGF)–b, and the ratio of IFN to TNF, were analyzed in 177 pedigrees from a community in Uganda with a high prevalence of TB. The heritability of these variables was estimated after adjustment for covariates, and TNF-a, in particular, had an estimated heritability of 68%. A principal component analysis of IFN-g, TNF-a, and TGF-b reflected the immunologic model of TB. In this analysis, the first component explained 138% of the variation in the data. This analysis illustrates the value of such intermediate phenotypes in mapping susceptibility loci for TB and demonstrates that this area deserves further research.
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    Linkage and association analysis of candidate genes for TB and TNFa cytokine expression: evidence for association with IFNGR1, IL-10, and TNF receptor 1 genes
    (Springer, 2007) Stein, Catherine M.; Zalwango, Sarah; Chiunda, Allan B.; Millard, Christopher; Leontiev, Dmitry V.; Horvath, Amanda L.; Cartier, Kevin C.; Chervenak, Keith; Boom, W. Henry; Elston, Robert C.; Mugerwa, Roy D.; Whalen, Christopher C.; Iyengar, Sudha K.
    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-a (TNFa) in response to culture filtrate as the phenotype. In the present study, we analyzed candidate genes related to TNFa regulation and found that interleukin (IL)-10, interferon-gamma receptor 1 (IFNGR1), and TNFa receptor 1 (TNFR1) genes were linked and associated to both TB and TNFa. 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.