title: Leprosy and the adaptation of human toll-like receptor 1.
abstract: 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.
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Sunny H
authors.initials: SH
authors.lastname: Wong
authors.forename: Sailesh
authors.initials: S
authors.lastname: Gochhait
authors.forename: Dheeraj
authors.initials: D
authors.lastname: Malhotra
authors.forename: Fredrik H
authors.initials: FH
authors.lastname: Pettersson
authors.forename: Yik Y
authors.initials: YY
authors.lastname: Teo
authors.forename: Chiea C
authors.initials: CC
authors.lastname: Khor
authors.forename: Anna
authors.initials: A
authors.lastname: Rautanen
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chapman
authors.forename: Tara C
authors.initials: TC
authors.lastname: Mills
authors.forename: Amit
authors.initials: A
authors.lastname: Srivastava
authors.forename: Aleksey
authors.initials: A
authors.lastname: Rudko
authors.forename: Maxim B
authors.initials: MB
authors.lastname: Freidin
authors.forename: Valery P
authors.initials: VP
authors.lastname: Puzyrev
authors.forename: Shafat
authors.initials: S
authors.lastname: Ali
authors.forename: Shweta
authors.initials: S
authors.lastname: Aggarwal
authors.forename: Rupali
authors.initials: R
authors.lastname: Chopra
authors.forename: Belum S N
authors.initials: BS
authors.lastname: Reddy
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Garg
authors.forename: Suchismita
authors.initials: S
authors.lastname: Roy
authors.forename: Sarah
authors.initials: S
authors.lastname: Meisner
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Hazra
authors.forename: Bibhuti
authors.initials: B
authors.lastname: Saha
authors.forename: Sian
authors.initials: S
authors.lastname: Floyd
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Keating
authors.forename: Cecilia
authors.initials: C
authors.lastname: Kim
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Fairfax
authors.forename: Julian C
authors.initials: JC
authors.lastname: Knight
authors.forename: Philip C
authors.initials: PC
authors.lastname: Hill
authors.forename: Richard A
authors.initials: RA
authors.lastname: Adegbola
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.forename: Paul E M
authors.initials: PE
authors.lastname: Fine
authors.forename: Ramasamy M
authors.initials: RM
authors.lastname: Pitchappan
authors.forename: Rameshwar N K
authors.initials: RN
authors.lastname: Bamezai
authors.forename: Adrian V S
authors.initials: AV
authors.lastname: Hill
authors.forename: Fredrik O
authors.initials: FO
authors.lastname: Vannberg
mesh_terms: 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
chemical_list: 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