02643nas a2200493   4500000000100000008004100001260001300042653001500055653001000070653000900080653002200089653001000111653002100121653001100142653001900153653003800172653001500210653001100225653001100236653002000247653001200267653000900279653001600288653002500304653003600329653002500365653001600390100001500406700001500421700001300436700001700449700001700466700001400483700001400497700002000511700001200531700001300543700001300556245009700569300001200666490000700678520145000685022001402135       2009                            d  c2009 Sep10aAdolescent10aAdult10aAged10aAged, 80 and over10aChild10aChild, Preschool10aFemale10aGene Frequency10aGenetic Predisposition to Disease10aHaplotypes10aHumans10aInfant10aInfant, Newborn10aleprosy10aMale10aMiddle Aged10aMycobacterium leprae10aPolymorphism, Single Nucleotide10aToll-Like Receptor 410aYoung Adult1 aBochud P-Y1 aSinsimer D1 aAderem A1 aSiddiqui M R1 aSaunderson P1 aBritton S1 aAbraham I1 aTadesse Argaw A1 aJaner M1 aHawn T R1 aKaplan G00aPolymorphisms in Toll-like receptor 4 (TLR4) are associated with protection against leprosy.  a1055-650 v283 a<p>Accumulating evidence suggests that polymorphisms in Toll-like receptors (TLRs) influence the pathogenesis of mycobacterial infections, including leprosy, a disease whose manifestations depend on host immune responses. Polymorphisms in TLR2 are associated with an increased risk of reversal reaction, but not susceptibility to leprosy itself. We examined whether polymorphisms in TLR4 are associated with susceptibility to leprosy in a cohort of 441 Ethiopian leprosy patients and 197 healthy controls. We found that two single nucleotide polymorphisms (SNPs) in TLR4 (896G>A [D299G] and 1196C>T [T399I]) were associated with a protective effect against the disease. The 896GG, GA and AA genotypes were found in 91.7, 7.8 and 0.5% of leprosy cases versus 79.9, 19.1 and 1.0% of controls, respectively (odds ratio [OR] = 0.34, 95% confidence interval [CI] 0.20-0.57, P < 0.001, additive model). Similarly, the 1196CC, CT and TT genotypes were found in 98.1, 1.9 and 0% of leprosy cases versus 91.8, 7.7 and 0.5% of controls, respectively (OR = 0.16, 95% CI 0.06--.40, P < 0.001, dominant model). We found that Mycobacterium leprae stimulation of monocytes partially inhibited their subsequent response to lipopolysaccharide (LPS) stimulation. Our data suggest that TLR4 polymorphisms are associated with susceptibility to leprosy and that this effect may be mediated at the cellular level by the modulation of TLR4 signalling by M. leprae.</p>  a1435-4373