Pulmonary tuberculosis: Gene discovery and functional analysis

Coordinator:    Prof. Dr. Rolf Horstmann
Institution: Bernhard-Nocht-Institute für Tropenmedizin
On the basis of the studies during the phases of NGFN1 and NGFN2 support, 2010 HIV-negative cases with confirmed pulmonary tuberculosis and 2346 healthy control individuals from Ghana are now available for ongoing genetic and functional analyses. Cases and controls are matched for age, gender and ethnic background. Fine-typing of mycobacterial isolates allowed detailed comparisons of the clinical phenotypes caused by either one of the main mycobacterial species, Mycobacterium tuberculosis or M. africanum. At the same time, the availability of genetic mycobacterial and human data enables analyses of host-pathogen interactions. Analyses of the candidate genes encoding VDR, IL1A/B, IL4, P2X7, SP110, CD1d, ICOS, DC-SIGN, CXCL5, SLC11A1, TNF-alpha and IFNGR1 as well as of genes relevant in the interferon-gamma signal cascade did not provide significant results. However, significant results were found for variants of the genes encoding IL10, ALOX5, MCP-1, MBL, IL-4R, TNFRSF1B and IRGM. The ALOX5 and MBL variants have meanwhile been characterized further in functional assays. Further functional studies are planned for an exonic IFNG variant that was identified in our study group, for SPP1 and for an IRGM variant that is associated with protection from TB exclusively caused by M. tuberculosis-EUAM isolates.
At the same time, the genome-wide analysis DNA from 1000 cases and 1100 control individuals  (Affymetrix SNP-Array 6.0) has been completed. Relevant SNPs identified were replicated in the Illumina system in the entire study group. Results were compared with study populations originating from Russia and Gambia. Currently, significant signals from these comparisons are subjected to further genetic analysis.
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