title: Toll-like receptor 1 N248S single-nucleotide polymorphism is associated with leprosy risk and regulates immune activation during mycobacterial infection.
abstract: 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.
authors.affiliation: Laboratório de Hanseníase, Instituto Oswaldo Cruz, Av. Brasil 4365, Manguinhos Rio de Janeiro, RJ, Brazil.
authors.forename: Carolinne de Sales
authors.initials: Cde S
authors.lastname: Marques
authors.forename: Vânia N
authors.initials: VN
authors.lastname: Brito-de-Souza
authors.forename: Luana Tatiana Albuquerque
authors.initials: LT
authors.lastname: Guerreiro
authors.forename: João H
authors.initials: JH
authors.lastname: Martins
authors.forename: Evaldo P
authors.initials: EP
authors.lastname: Amaral
authors.forename: Cynthia C
authors.initials: CC
authors.lastname: Cardoso
authors.forename: Ida Maria Foschiani
authors.initials: IM
authors.lastname: Dias-Batista
authors.forename: Weber Laurentino da
authors.initials: WL
authors.lastname: Silva
authors.forename: José Augusto C
authors.initials: JA
authors.lastname: Nery
authors.forename: Priscila
authors.initials: P
authors.lastname: Medeiros
authors.forename: Patricia
authors.initials: P
authors.lastname: Gigliotti
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Campanelli
authors.forename: Marcos
authors.initials: M
authors.lastname: Virmond
authors.forename: Euzenir Nunes
authors.initials: EN
authors.lastname: Sarno
authors.forename: Marcelo T
authors.initials: MT
authors.lastname: Mira
authors.forename: Francisco C F
authors.initials: FC
authors.lastname: Lana
authors.forename: Ernesto Raúl
authors.initials: ER
authors.lastname: Caffarena
authors.forename: Antonio G
authors.initials: AG
authors.lastname: Pacheco
authors.forename: Ana Carla
authors.initials: AC
authors.lastname: Pereira
authors.forename: Milton Ozório
authors.initials: MO
authors.lastname: Moraes
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005787:Gene Frequency / Q000235:genetics; D005838:Genotype; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D007109:Immunity / Q000235:genetics; D007918:Leprosy / Q000235:genetics* / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008875:Middle Aged; D009166:Mycobacterium leprae / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics* / Q000502:physiology; D012307:Risk Factors; D051194:Toll-Like Receptor 1 / Q000235:genetics* / Q000502:physiology
chemical_list: D051194:Toll-Like Receptor 1
keywords: IL-10; N248S; SNPs; TLR1; TNF; cytokine; leprosy