Twin studies provide the most convincing evidence that host genes determine the outcome of infection in tuberculosis. Diehl & von Verscheur (1936) found that concordance among 80 monozygous twin pairs was 65%, compared with only 25% in 125 dizygous twin pairs. Kallman & Reisner (1942) similarly found higher concordance for tuberculosis among monozygous compared to dizygous twins (88% among 78 monozygous compared to 28% among 230 dizygous). In Comstock's reanalysis of the Prophit study the overall concordances were lower but again the rate was higher among monozygous twins (33% in 54 monozygous twin pairs and 14% in 148 dizygous; Comstock 1978).
Evidence that genetic factors are important in the resistance and susceptibility of animals to mycobacteria has accumulated from studies on rabbits and mice. The classic studies of Lurie showed that inbred families of rabbits can be divided into two distinct groups with markedly different susceptibilities to mycobacteria. Following infection with a virulent strain of Mycobacterium bovis the resistant rabbits developed cavitary pulmonary disease and the susceptible rabbits developed widespread haematogenously disseminated disease (Lurie 1941). When infected with human-type M. tuberculosis the resistant rabbits were able to inactivate more tubercle bacilli than the susceptible rabbits (Lurie et al 1952). The segregation pattern of the almost all-or-none nature of the observed resistance led Lurie to conclude that resistance was under genetic control.
Studies on inbred strains of mice have identified two distinct phenotypes in terms of resistance to Leishmania, Salmonella and mycobacteria, designated Bcgr and Bcgs for resistant and susceptible, respectively (reviewed in Blackwell 1989). A candidate gene for Bcg has been isolated by positional cloning and designated Nrampl (natural resistance-associated macrophage protein 1; Vidal et al 1993). A single non-conservative amino acid substitution of glycine by aspartic acid at position 169 has been shown to correlate with the Bcgs phenotype in 27 inbred mouse strains (Malo et al 1994). That Nrampl and not a closely linked gene is responsible for the Bcg phenotype has been proven by the production of a knockout mouse that is phenotypically identical to the homozygous Nramp1D169 mouse (Vidal et al 1995) and by restoration of the resistance phenotype in transgenic mice in which the Nramp1G169 allele was transferred onto the background of the homozygous Nramp1D169 genotype (Govoni et al 1996). The human homologue of the Nrampl gene, designated NRAMP1, has been cloned and mapped to human chromosome 2q35 (Cellier et al 1994). Several polymorphisms have been described in NRAMP1 (Liu et al 1995), and in this chapter we summarize data showing that NRAMP1 gene variants are associated with human tuberculosis.
Mice with targeted gene disruptions of the genes encoding y-interferon (IFN-y; Cooper et al 1993), the IFN-y receptor (Kamijo et al 1993) and microglobulin (Flynn et al 1992) have also been found to be highly susceptible to mycobacteria. These genes represent important candidate genes for tuberculosis studies in the human population.
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