TY - JOUR KW - Adult KW - Case-Control Studies KW - Enzyme-Linked Immunosorbent Assay KW - Female KW - Flow Cytometry KW - Gene Frequency KW - genotype KW - Haplotypes KW - Heterozygote KW - Humans KW - Immunity KW - leprosy KW - Leukocytes, Mononuclear KW - Middle Aged KW - Mycobacterium leprae KW - Polymorphism, Single Nucleotide KW - Risk Factors KW - Toll-Like Receptor 1 AU - Sales Marques C AU - Brito-de-Souza V AU - Guerreiro LTA AU - Martins J AU - Amaral E AU - Cardoso C AU - Dias-Batista IMF AU - Silva WL AU - Nery JA AU - Medeiros P AU - Gigliotti P AU - Campanelli AP AU - Virmond M AU - Sarno E AU - Mira MT AU - Lana F AU - Caffarena ER AU - Pacheco A AU - Pereira AC AU - Moraes M AB -

Conflicting findings about the association between leprosy and TLR1 variants N248S and I602S have been reported. Here, we performed case-control and family based studies, followed by replication in 2 case-control populations from Brazil, involving 3162 individuals. Results indicated an association between TLR1 248S and leprosy in the case-control study (SS genotype odds ratio [OR], 1.81; P = .004) and the family based study (z = 2.02; P = .05). This association was consistently replicated in other populations (combined OR, 1.51; P < .001), corroborating the finding that 248S is a susceptibility factor for leprosy. Additionally, we demonstrated that peripheral blood mononuclear cells (PBMCs) carrying 248S produce a lower tumor necrosis factor/interleukin-10 ratio when stimulated with Mycobacterium leprae but not with lipopolysaccharide or PAM3cysK4. The same effect was observed after infection of PBMCs with the Moreau strain of bacillus Calmette-Guerin but not after infection with other strains. Finally, molecular dynamics simulations indicated that the Toll-like receptor 1 structure containing 248S amino acid is different from the structure containing 248N. Our results suggest that TLR1 248S is associated with an increased risk for leprosy, consistent with its hypoimmune regulatory function.

BT - The Journal of infectious diseases C1 - http://www.ncbi.nlm.nih.gov/pubmed/23547143?dopt=Abstract CN - SALESMARQUEZ213 DA - 2013 Jul DO - 10.1093/infdis/jit133 IS - 1 J2 - J. Infect. Dis. LA - eng N2 -

Conflicting findings about the association between leprosy and TLR1 variants N248S and I602S have been reported. Here, we performed case-control and family based studies, followed by replication in 2 case-control populations from Brazil, involving 3162 individuals. Results indicated an association between TLR1 248S and leprosy in the case-control study (SS genotype odds ratio [OR], 1.81; P = .004) and the family based study (z = 2.02; P = .05). This association was consistently replicated in other populations (combined OR, 1.51; P < .001), corroborating the finding that 248S is a susceptibility factor for leprosy. Additionally, we demonstrated that peripheral blood mononuclear cells (PBMCs) carrying 248S produce a lower tumor necrosis factor/interleukin-10 ratio when stimulated with Mycobacterium leprae but not with lipopolysaccharide or PAM3cysK4. The same effect was observed after infection of PBMCs with the Moreau strain of bacillus Calmette-Guerin but not after infection with other strains. Finally, molecular dynamics simulations indicated that the Toll-like receptor 1 structure containing 248S amino acid is different from the structure containing 248N. Our results suggest that TLR1 248S is associated with an increased risk for leprosy, consistent with its hypoimmune regulatory function.

PY - 2013 SP - 120 EP - 9 T2 - The Journal of infectious diseases TI - Toll-like receptor 1 N248S single-nucleotide polymorphism is associated with leprosy risk and regulates immune activation during mycobacterial infection. VL - 208 SN - 1537-6613 ER -