TY - JOUR
KW - Gene Frequency
KW - Genetic Predisposition to Disease
KW - Genome-Wide Association Study
KW - HLA-DQ Antigens
KW - HLA-DQ alpha-Chains
KW - HLA-DR Antigens
KW - HLA-DRB1 Chains
KW - Humans
KW - leprosy
KW - Mycobacterium leprae
KW - Toll-Like Receptor 1
AU - Wong S
AU - Gochhait S
AU - Malhotra D
AU - Pettersson F
AU - Teo Y
AU - Khor CC
AU - Rautanen A
AU - Chapman SJ
AU - Mills TC
AU - Srivastava AK
AU - Rudko A
AU - Freidin M
AU - Puzyrev VP
AU - Ali S
AU - Aggarwal S
AU - Chopra R
AU - Reddy BS N
AU - Garg V
AU - Roy S
AU - Meisner S
AU - Hazra S
AU - Saha B
AU - Floyd S
AU - Keating B
AU - Kim C
AU - Fairfax B
AU - Knight JC
AU - Hill P
AU - Adegbola RA
AU - Hakonarson H
AU - Fine PE
AU - Pitchappan R
AU - Bamezai R
AU - Hill A
AU - Vannberg F
AB - <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>
BT - PLoS pathogens
C1 - http://www.ncbi.nlm.nih.gov/pubmed/20617178?dopt=Abstract
DA - 2010 Jul 01
DO - 10.1371/journal.ppat.1000979
J2 - PLoS Pathog.
LA - eng
N2 - <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>
PY - 2010
EP - e1000979
T2 - PLoS pathogens
TI - Leprosy and the adaptation of human toll-like receptor 1.
VL - 6
SN - 1553-7374
ER -