02953nas a2200673   4500000000100000008004100001260001600042653001900058653003800077653003400115653002000149653002400169653002000193653002000213653001100233653001200244653002500256653002500281100001100306700001500317700001500332700001700347700001000364700001200374700001500386700001500401700001300416700001800429700001200447700001400459700001500473700001000488700001500498700001300513700001500526700001100541700001000552700001400562700001200576700001100588700001200599700001400611700001000625700001400635700001400649700001100663700001600674700001700690700001200707700001700719700001400736700001100750700001500761245006200776300001300838490000600851520140800857022001402265       2010                            d  c2010 Jul 0110aGene Frequency10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHLA-DQ Antigens10aHLA-DQ alpha-Chains10aHLA-DR Antigens10aHLA-DRB1 Chains10aHumans10aleprosy10aMycobacterium leprae10aToll-Like Receptor 11 aWong S1 aGochhait S1 aMalhotra D1 aPettersson F1 aTeo Y1 aKhor CC1 aRautanen A1 aChapman SJ1 aMills TC1 aSrivastava AK1 aRudko A1 aFreidin M1 aPuzyrev VP1 aAli S1 aAggarwal S1 aChopra R1 aReddy BS N1 aGarg V1 aRoy S1 aMeisner S1 aHazra S1 aSaha B1 aFloyd S1 aKeating B1 aKim C1 aFairfax B1 aKnight JC1 aHill P1 aAdegbola RA1 aHakonarson H1 aFine PE1 aPitchappan R1 aBamezai R1 aHill A1 aVannberg F00aLeprosy and the adaptation of human toll-like receptor 1.  ae10009790 v63 a<p>Leprosy is an infectious disease caused by the obligate intracellular pathogen Mycobacterium leprae and remains endemic in many parts of the world. Despite several major studies on susceptibility to leprosy, few genomic loci have been replicated independently. We have conducted an association analysis of more than 1,500 individuals from different case-control and family studies, and observed consistent associations between genetic variants in both TLR1 and the HLA-DRB1/DQA1 regions with susceptibility to leprosy (TLR1 I602S, case-control P = 5.7 x 10(-8), OR = 0.31, 95% CI = 0.20-0.48, and HLA-DQA1 rs1071630, case-control P = 4.9 x 10(-14), OR = 0.43, 95% CI = 0.35-0.54). The effect sizes of these associations suggest that TLR1 and HLA-DRB1/DQA1 are major susceptibility genes in susceptibility to leprosy. Further population differentiation analysis shows that the TLR1 locus is extremely differentiated. The protective dysfunctional 602S allele is rare in Africa but expands to become the dominant allele among individuals of European descent. This supports the hypothesis that this locus may be under selection from mycobacteria or other pathogens that are recognized by TLR1 and its co-receptors. These observations provide insight into the long standing host-pathogen relationship between human and mycobacteria and highlight the key role of the TLR pathway in infectious diseases.</p>  a1553-7374