Genetics | Tuberculosis Research Unit

Research Challenges

The TBRU genetics studies seek to understand how host immunity genes influence the immune response to M. tuberculosis and the development of latent M. tuberculosis infection and active tuberculosis (TB) disease.

The general objective of the Genetics Component of the TBRU is to bring together expertise in human genetics across sites and studies for TBRU\x92s research agenda, in order to take a variety of approaches to studying host genetics of TB.

Specific Objectives Include:

To identify host genes associated with latent infection and progression to active disease
To identify host genes associated with different immune responses in vitro
To use a variety of approaches to examine host genetics, including genome scans, candidate gene studies, and microarray studies

Organization and Operation

Genetic studies are conducted both at CWRU under the direction of Dr. Catherine Stein and at the University of Washington by Dr. Thomas Hawn. There are also efforts to transfer as much lab technology as possible to the labs at the field sites.

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Protocol Number	Study Title	Short Study Title	Project Site	Status
DMID 01-005	Kawempe Community Health Study	KCHS	Uganda	Active
	The Role of Innate Immune Responses, and of Genetic Determinants of Innate Immune Responses, in BCG Vaccination-induced Protection Against Childhood TB	Innate Immunity	South Africa	Active
	Predictors of Immune Response and Progression to TB Disease in Infants Vaccinated at Birth with BCG	Infant Predictors	South Africa	Active

Genetics research at CWRU is conducted at the Sequencing and Genotyping Core Facility, in the Department of Genetics. This facility has 2 ABI 3100 and 1 ABI 3730 DNA analyzers. This Facility also has facilities for microsatellite and SNP genotyping, including an Illumina Beadstation. The Illumina platform analyzes genomic DNA in 96 well plates. Custom-order BeadArrays are constructed containing 384, 768, or 1536 SNPs per bead (or multiples of these), resulting in a high-throughput analysis. The lab also has iSelect, which can perform genotyping of thousands of SNPs simultaneously, and TaqMan platforms. Genotypes from these analyses will be used in studies examining the association between TB and human susceptibility gene polymorphisms. This laboratory also has Illumina/Solexa sequencing capability. CWRU also has microarray analysis facilities.

Currently, DNA extraction procedures have been conducted at service laboratories at CWRU. These procedures will be moved to the JCRC Immunology laboratory.

Statistical analyses are directed by Dr. Stein in the Division of Genetic and Molecular Epidemiology, Department of Epidemiology and Biostatistics. Statistical Analysis of Genetic Epidemiology (S.A.G.E.) software is programmed in this Department, under the direction of Dr. Robert Elston. This provides outstanding statistical genetic expertise and computational power for the analysis of genetic data. Analysis models include linkage analysis, genetic association analysis, and haplotype construction. The Department also provides a large number of high powered computer processors specifically purchased for developing genetic analysis software and performing genetic analyses.

Genetics research at the University of Washington is conducted at the Institute for Systems Biology. This lab laboratory includes an Applied Biosystems 3730 capillary electrophoresis DNA sequencer and a Sequenom genotyping platform based on the MassARRAY™ technique.