This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Tuberculosis (TB) is a growing public health problem. Several studies suggest a role for host genetics in disease susceptibility, but studies to date have been inconsistent and a comprehensive genetic model has not yet emerged. A limitation of previous genetic studies is that they only analyzed the binary trait TB, which does not reflect disease heterogeneity. Furthermore, these studies have not accounted for the influence of shared environment within households on TB risk, which may spuriously inflate estimates of heritability. We conducted a household contact study in a TB-endemic community in Uganda. Previously, we estimated the heritability of three cytokines as endophenotypes for TB: interferon-gamma, tumor necrosis factor-alpha (TNF), and transforming growth factor-beta. Using both standard heritability estimation methods and path analysis, we found that TNF has a high heritability (66%) and very small influence of shared environment. Segregation analysis of TNF showed that a major gene effect explained one-third of the phenotypic variance of TNF. Recently, we have completed a candidate gene study, and found that SNPs in IL10, TNFR1, and IFNGR1 are associated with both TNF and TB. In addition, we found that the effect of TNFR1 or TB risk is modified by HIV status. We are completing a genome-wide linkage scan, and our analyses have shown linkage between these traits and previously characterized candidate gene regions as well as novel regions. Future analyses will include fine mapping and analysis of new candidate gene pathways.
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