Leprosy, Susceptibility To, 5
A number sign (#) is used with this entry because this form of susceptibility to leprosy (LPRS5) is associated with a polymorphism in the TLR1 gene (601194). A polymorphism in the TLR1 gene is also associated with protection against leprosy.
See 609888 for a discussion of leprosy susceptibility in general and information on genetic heterogeneity.
MappingLPRS5 is associated with a polymorphism in the TLR1 gene, which Taguchi et al. (1996) mapped to chromosome 4p14.
Molecular GeneticsSchuring et al. (2009) studied association of an asn248-to-ser (N248S; 601194.0002) SNP in the TLR1 gene and leprosy in a Bangladeshi population consisting of 842 patients and 543 controls. They found that the S allele was slightly more frequent among patients than controls (54% vs 51%; OR = 1.12). Homozygosity for S248 was significantly associated with leprosy per se (OR = 1.34), whereas heterozygosity was found to be protective against leprosy (OR = 0.78). In contrast, the homozygous N248 genotype was equally distributed among patients and controls. No difference in allele frequency or genotype was associated with leprosy classification or serologic status. However, patients who experienced erythema nodosum leprosum reactions were more likely to have the N248 allele (68%) than were patients who had no reactions (46%). Schuring et al. (2009) noted that amino acid 248 of TLR1 is located in the external ligand-binding site of the receptor, and that Omueti et al. (2007) had shown that the S248 variant enabled normal function, whereas the N248 variant diminished the response of TLR1 to bacterial agonists.
Protection Against Leprosy
Johnson et al. (2007) identified a nonsynonymous SNP in TLR1, 1805T-G, that results in an ile602-to-ser (I602S; 601194.0001) substitution at the junction of the transmembrane and intracellular domains of TLR1. They found that 602S was associated with aberrant trafficking of TLR1 to the cell surface and diminished responses of blood monocytes to bacterial agonists. The 602S allele was more frequent in 66 Europeans (75% allele frequency) than in 27 Africans (26%) or in 21 East Asians, all of whom were homozygous for 602I. Johnson et al. (2007) found that the 602S allele was significantly underrepresented in 57 Turkish leprosy patients compared with 90 controls (odds ratio of 0.48). Leprosy patients were more frequently homozygous for 602I, whereas control subjects were more likely to be homozygous for 602S. The results suggested that TLR1 602S plays a protective role in the context of clinical leprosy.
Using luciferase reporter analysis, Misch et al. (2008) observed reduced NFKB (see 164011) activity in embryonic kidney cells transfected with the 1805G TLR1 variant following stimulation with extracts of M. leprae compared with cells transfected with the 1805T TLR1 variant. Peripheral blood mononuclear cells from individuals homozygous for 1805G had significantly reduced proinflammatory cytokine responses following stimulation with whole M. leprae or cell wall extracts. In 933 Nepalese leprosy patients, including 238 with the inflammatory reversal reaction, the 1805G allele was associated with protection from reversal reaction (OR of 0.51). Misch et al. (2008) proposed that TLR1 may be associated with a Th1 response and that TLR1 deficiency due to 1805G influences adaptive immunity during leprosy infection and may affect clinical manifestations, such as nerve damage and disability.