Leprosy and the adaptation of human toll-like receptor 1.
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.
Wong
Sunny H
SH
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
Gochhait
Sailesh
S
Malhotra
Dheeraj
D
Pettersson
Fredrik H
FH
Teo
Yik Y
YY
Khor
Chiea C
CC
Rautanen
Anna
A
Chapman
Stephen J
SJ
Mills
Tara C
TC
Srivastava
Amit
A
Rudko
Aleksey
A
Freidin
Maxim B
MB
Puzyrev
Valery P
VP
Ali
Shafat
S
Aggarwal
Shweta
S
Chopra
Rupali
R
Reddy
Belum S N
BS
Garg
Vijay K
VK
Roy
Suchismita
S
Meisner
Sarah
S
Hazra
Sunil K
SK
Saha
Bibhuti
B
Floyd
Sian
S
Keating
Brendan J
BJ
Kim
Cecilia
C
Fairfax
Benjamin P
BP
Knight
Julian C
JC
Hill
Philip C
PC
Adegbola
Richard A
RA
Hakonarson
Hakon
H
Fine
Paul E M
PE
Pitchappan
Ramasamy M
RM
Bamezai
Rameshwar N K
RN
Hill
Adrian V S
AV
Vannberg
Fredrik O
FO
D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006683:HLA-DQ Antigens / Q000235:genetics; D059848:HLA-DQ alpha-Chains; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006801:Humans; D007918:Leprosy / Q000235:genetics* / Q000276:immunology; D009166:Mycobacterium leprae / Q000276:immunology; D051194:Toll-Like Receptor 1 / Q000235:genetics* / Q000276:immunology
D006683:HLA-DQ Antigens; D059848:HLA-DQ alpha-Chains; C069050:HLA-DQA1 antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D051194:Toll-Like Receptor 1