Pathway Analysis of Tuberculosis Pathogenesis


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

Published Papers:

Baker AR, Zalwango S, Malone LL, Igo Jr RP, Qui F, Nsereko M, Adams MD, Supelak P, Mayanja-Kizza H, Boom WH, Stein CM.  Genetic susceptibility to tuberculosis associated the CTSZ haplotypes in Uganda household contact study. Hum Immunol 2011; 72:426-430. PMCID: PMC3078986.

Baker AR, Qui F, Randhawa AK, Horne DJ, , Adams MD, Shey M, Barnholtz-Sloan J,  Mayanja-Kizza H, Kaplan G, Hanekom WA, Boom WH, Hawn TR, Stein CM.  Genetic variation in TLR genes in Uganda and South African populations and comparison with HapMap data.  PLoS One 2012; 7:347597.  PMCID: PMC3480404.

Qiu F, Stein CM, Elston RC. Joint modeling of longitudinal data and discrete-time survival outcome. Stat Methods Med Res. 2016; 25:1512-1526. PMCID: PMC3830602.

Hall NB, Igo RP, Malone LL, Truitt B, Schnell A, Tao L, Qiu F, Okwera B, Nsereko M, Chervenak K, Lancioni C, Hawn TR, Mayanja-Kizza H. Joloba ML, Boom WH, Stein CM. Polymorphisms in TICAM2 and IL1B are associated with TB.  Genes Immuno 2015; 16:127-133. PMCID: PMC4352113.

Sobota RS, Stein CM, Kodaman N, Scheinfeldt LB, Maro I, Wieland-Alter W, Igo Jr. RP, Magohe A, Malone LL, Chervenak K, Hall NB, Modongo C, Zetola N, Matee M, Joloba M, Froment A, Nyambo T, Moore JH, Scott WK Lahey T, Boom WH, von Reyn CF, Tishkoff SA, Sirugo G, Williams SM. A locus at 5q33.3 confers resistance to tuberculosis in highly susceptible patients.  Am J Hum Genet 2016; 98:514-524.

Stein CM, Morris NJ, Hall NB, Nock NL. Structural equation modeling. In: Statistical Human Genetics: Methods and Protocols, second edition. Elston RC, ed.  Humana Press.