Genetic Studies of Human Susceptibility to Tuberculosis

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant)
Tuberculosis (TB) is currently and historically an enormous public health
problem. Approximately one-third of the world's population are currently
infected with Mycobacterium tuberculosis (M. tuberculosis) and TB accounts for
over 25% of preventable adult deaths world-wide. Despite the high infection
rate, only about 10% of people infected with M.tb ever become sick with active
TB. Evidence suggests that progression to active TB is influenced by host
genetic factors. For example, the epidemiology of TB suggests that genetic
selection takes place after introduction of M. tuberculosis to the population;
genetically susceptible individuals succumb to the infection and relatively
resistant individuals survive to reproduce. As well, twin studies demonstrate
higher concordance rates for TB among identical twins, compared to fraternal
twins. Mouse models of mycobacterial infection have identified several
potential susceptibility loci, such as the gene named Nramp1, as well as
several cytokine and cytokine receptor genes. Family-based linkage studies and
case-control studies of candidate genes in humans suggest roles for these and
other genes associated with development of TB in humans. In light of these
observations, we propose a family-based association study of candidate genes
for TB susceptibility. To accomplish the goal of identifying genes influencing
susceptibility to TB we specifically propose to: 1) Ascertain 1,000 parent-
child triads (500 Caucasian, 500 African-American) from North and South
Carolina for genetic studies of TB susceptibility genes. 2) Test candidate
genes in the first 500 parent-child triads. Multiple single nucleotide
polymorphisms (SNPs) will be genotyped in each gene and analyzed using family-
based tests of association; significant results will be followed-up in the
remaining 500 triads. 3) Examine the relationship between candidate genes and
other clinical variables such as PPD skin test results, disease severity,
treatment relapse and failure, and presence of extrapulmonary disease. 4)
Evaluate gene-gene and gene-environment interactions using multivariable
models and data reduction techniques such as the multifactor dimensionality
reduction (MDR) method.
StatusFinished
Effective start/end date9/10/017/31/07

Funding

  • National Heart, Lung, and Blood Institute: $462,000.00
  • National Heart, Lung, and Blood Institute: $462,000.00
  • National Heart, Lung, and Blood Institute: $462,000.00
  • National Heart, Lung, and Blood Institute: $462,000.00
  • National Heart, Lung, and Blood Institute: $462,000.00

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