Leprosy, Susceptibility To, 4
A number sign (#) is used with this entry because susceptibility to early-onset leprosy is associated with a polymorphism in the LTA gene (153440) on chromosome 6p21.3. This polymorphism accounts, in part, for susceptibility to leprosy linked to chromosome 6p21.3 (LPRS4). However, additional genetic risk factors likely underlie susceptibility to leprosy linked to chromosome 6p21.3.
See 609888 for a discussion of leprosy susceptibility in general and information on genetic heterogeneity.
MappingMira et al. (2003) detected a linkage peak associated with leprosy in the 6p21 chromosomal region, which fine mapping placed close to D6S2427 (lod = 2.7).
In a 2-stage genomewide scan of 71 multicase leprosy families (365 individuals) in Brazil, Miller et al. (2004) found suggestive evidence for linkage to chromosomes 6p21.32, 17q22, and 20p13. Peak lod scores for these regions were 3.23 (p of 5.8 x 10(-5)), 2.38 (p of 0.0005), and 1.51 (p of 0.004), respectively. The peak lod score for chromosome 6p21.32 was obtained at HLA-DQA (146880).
Molecular GeneticsLTA Polymorphism and Susceptibility to Early-Onset Leprosy
Alcais et al. (2007) reported the linkage disequilibrium mapping of the linkage peak on chromosome 6p21 reported by Mira et al. (2003). In both a Vietnamese familial sample and an Indian case-control sample, the low-producing lymphotoxin-alpha (LTA)+80 A allele (153440.0003) was significantly associated with an increase in leprosy risk. Analysis of an additional case-control sample from Brazil and an additional familial sample from Vietnam showed that the LTA+80 effect was much stronger in young individuals. Alcais et al. (2007) stated that their results showed that LTA+80 did not have a substantial role in leprosy susceptibility in individuals over 25 years of age. The A allele of LTA+80 is associated with significantly lower levels of a downstream reporter than the C allele (Knight et al., 2004). The findings of Alcais et al. (2007) demonstrated that low levels of LTA production are associated with a higher risk of leprosy. This result is consistent with studies in animal models linking disruption of the LTA pathway with an increase in susceptibility to intracellular pathogens.
Polymorphisms in Other Genes on Chromosome 6p21.3
Moraes et al. (2001) found that a polymorphism in the TNF gene (191160.0004) on chromosome 6p21.3 was significantly associated with a stronger response (Mitsuda reaction) to lepromin in borderline tuberculoid leprosy patients. Epigenetic factors such as a history of BCG vaccination or a reversal reaction, but not both, were also associated with boosted Mitsuda reactions. Moraes et al. (2001) concluded that augmented TNF production may be associated with the TNF2 allele and an increased granulomatous response.