Identifying genetic susceptibility factors for tuberculosis in Africans: acombined approach using a candidate gene study and a genome-wide screen

There is convincing evidence that host genes affect the outcome of infectio n in human tuberculosis. Two complementary strategies were used to identify the genes involved. A linkage-based genome-wide screen was carried out to locate the positions of genes exerting a major population-wide effect on tu berculosis susceptibility. A candidate-gene-based case-control study was us ed to examine the effects of genes that may exert a more moderate effect on risk of clinical tuberculosis. The genome screen was conducted in two stag es. In the first stage 299 microsatellite markers, spanning all 23 chromoso mes, were typed in 92 independent sib-pairs, and seven regions showed some evidence of co-segregation with the disease. These seven regions were exami ned in a second set of 81 sib-pairs, and markers on chromosomes 15q and Xq showed evidence of linkage to tuberculosis. An X chromosome susceptibility gene may contribute to the excess of males with tuberculosis observed in ma ny populations. The candidate gene approach compared the frequency of polym orphisms in several genes in over 400 subjects with smear-positive pulmonar y tuberculosis and 400 ethnically matched healthy controls. Polymorphisms i n genes encoding natural-resistance-associated macrophage protein, vitamin D receptor and mannose-binding lectin were associated with tuberculosis. Th ese results suggest that many genes may be involved in determining host sus ceptibility to tuberculosis, and highlight the importance of using several different study methods to locate them.