Pathway Analysis of Tuberculosis Pathogenesis

Information:

Sponsor - U.S. National Institutes of Health (R01-HL096811)
Principal Investigator - Catherine Stein, PhD, CWRU

Type of Study Observational
Design Longitudinal family-based study - uses subjects in the Kawempe Community Health Study (KCHS)
Project Site Uganda
Sample Size 1,400
Population Adults with culture confirmed active tuberculosis and their household contacts
Study Period 2004-2010
Interactions This study utilizes stored buffy coat and PBMC samples from KCHS study participants. Collaborating investigators, utilizing shared JCRC laboratory infrastructure.

Goal of Study:

The goal of the study is to investigate host genetic and immunologic predictors of resistance to M. tuberculosis infection and progression from latent M. tuberculosis infection to active tuberculosis disease. The pathogenesis of TB will then be modeled using a structural equation modeling approach that accounts for relationships between individuals in a household.

Objectives of Study:

  1. To examine genetic influences on resistance to Mtb infection and progression from latent infection to active disease. This will be achieved by fine mapping chromosomal regions identified through a genome wide scan and analyzing specific genes identified through the genome scan as well as innate immunity pathway genes
  2. To characterize immunological variables associated with resistance to infection. This will be done by analyzing cytokine responses to three ligands that are recognized by the innate immune response during Mtb infection
  3. To model pathogenesis of TB using structural equation modeling (SEM). We have recently developed a method to utilize family data within a SEM framework, and as part of this study objective, we will produce software implementing this method that will be available for public use