This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for 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. Recently, we have completed a whole-genome linkage scan. This analysis identified two regions linked to TB at the suggestive level (p<.0001), fine mapping analysis of these regions is ongoing. We also observed suggestive linkage between two novel regions and resistance to M. tuberculosis infection. Further analyses will include fine mapping of these regions as well as candidate gene pathways.
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