02832nas a2200589   4500000000100000008004100001260001300042653001000055653002500065653003800090653001100128653001900139653001900158653001300177653001500190653001700205653001100222653001300233653001200246653002800258653001600286653002500302653003600327653001700363653002500380100002000405700002100425700001800446700001400464700001300478700001400491700002100505700001300526700001200539700001500551700001600566700001800582700001400600700001200614700001200626700001100638700001700649700001400666700001500680700001300695245015800708300001000866490000800876050002000884520132400904022001402228       2013                            d  c2013 Jul10aAdult10aCase-Control Studies10aEnzyme-Linked Immunosorbent Assay10aFemale10aFlow Cytometry10aGene Frequency10agenotype10aHaplotypes10aHeterozygote10aHumans10aImmunity10aleprosy10aLeukocytes, Mononuclear10aMiddle Aged10aMycobacterium leprae10aPolymorphism, Single Nucleotide10aRisk Factors10aToll-Like Receptor 11 aSales Marques C1 aBrito-de-Souza V1 aGuerreiro LTA1 aMartins J1 aAmaral E1 aCardoso C1 aDias-Batista IMF1 aSilva WL1 aNery JA1 aMedeiros P1 aGigliotti P1 aCampanelli AP1 aVirmond M1 aSarno E1 aMira MT1 aLana F1 aCaffarena ER1 aPacheco A1 aPereira AC1 aMoraes M00aToll-like receptor 1 N248S single-nucleotide polymorphism is associated with leprosy risk and regulates immune activation during mycobacterial infection.  a120-90 v208  aSALESMARQUEZ2133 a<p>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.</p>  a1537-6613