Browsing by Author "Chervenak, Keith"

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    Genetic and Shared Environmental Influences on Interferon-g Production in Response to Mycobacterium tuberculosis Antigens in a Ugandan Population
    (The American Society of Tropical Medicine and Hygiene, 2010) Tao, Li; Zalwango, Sarah; Chervenak, Keith; Thiel, Bonnie; Malone, LaShaunda L.; Feiyou, Qiu; Mayanja-Kizza, Harriet; Boom, Henry; Stein, Catherine M.
    Interferon-g (IFN-g) is a key cytokine in the immune response to Mycobacterium tuberculosis (Mtb). Many studies established IFN-g responses are influenced by host genetics, however differed widely by the study design and heritability estimation method. We estimated heritability of IFN-g responses to Mtb culture filtrate (CF), ESAT-6, and Antigen 85B (Ag85B) in 1,104 Ugandans from a household contact study. Our method separately evaluates shared environmental and genetic variance, therefore heritability estimates were not upwardly biased, ranging from 11.6% for Ag85B to 22.9% for CF. Subset analyses of individuals with latent Mtb infection or without human immunodeficiency virus infection yielded higher heritability estimates, suggesting 10–30% of variation in IFN-g is caused by a shared environment. Immunosuppression does not negate the role of genetics on IFN-g response. These estimates are remarkably close to those reported for components of the innate immune response. These findings have implications for the interpretation of IFN-g response assays and vaccine studies.
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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.
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    Long-term Stability of Resistance to Latent Mycobacterium tuberculosis Infection in Highly Exposed Tuberculosis Household Contacts in Kampala, Uganda
    (Clinical Infectious Diseases, 2019) Stein, Catherine M.; Nsereko, Mary; Malone, LaShaunda L.; Okware, Brenda; Kisingo, Hussein; Nalukwago, Sophie; Chervenak, Keith; Mayanja-Kizza, Harriet; Hawn, Thomas R.; Boom, W. Henry
    Resistance to latent Mycobacterium tuberculosis (M.tb) infection, identified by persistently negative tuberculin skin tests (TST) and interferon-gamma release assays (IGRA), after close contact with pulmonary tuberculosis (TB) patients has not been extensively characterized. Stability of this “resistance” beyond 2 years from exposure is unknown. Methods. 407 of 657 eligible human immunodeficiency virus (HIV)-negative adults from a TB household contact study with persistently negative TST (PTST−) or with stable latent M.tb infection (LTBI) were retraced 9.5 years (standard deviation = 3.2) later. Asymptomatic retraced contacts underwent 3 IGRAs and follow-up TST, and their M.tb infection status classified as definite/ possible/probable. Results. Among PTST− with a definite classification, 82.7% were concordantly TST−/ quantiferon-TB Gold− (QFT−), and 16.3% converted to TST+/QFT+ LTBI. Among original LTBI contacts, 83.6% remained LTBI, and 3.9% reverted their TST and were QFT−. Although TST and QFT concordance was high (κ = 0.78), 1.0% of PTST and 12.5% of original LTBI contacts could not be classified due to discordant TST and QFT results. Epidemiological variables did not differ between retraced PTST− and LTBI contacts. Conclusion. Resistance to LTBI, defined by repeatedly negative TST and IGRA, in adults who have had close contact with pulmonary TB patients living in TB-endemic areas, is a stable outcome of M.tb exposure. Repeated longitudinal measurements with 2 different immune assays and extended follow-up provide enhanced discriminatory power to identify this resister phenotype and avoid misclassification. Resisters may use immune mechanisms to control aerosolized M.tb that differ from those used by persons who develop “classic” LTBI.