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 analys...
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oai:doaj.org-article:64063bfbf0014cd68c02a3a26d68c81c2021-12-02T20:00:31ZLeprosy and the adaptation of human toll-like receptor 1.1553-73661553-737410.1371/journal.ppat.1000979https://doaj.org/article/64063bfbf0014cd68c02a3a26d68c81c2010-07-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20617178/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Leprosy 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.Sunny H WongSailesh GochhaitDheeraj MalhotraFredrik H PetterssonYik Y TeoChiea C KhorAnna RautanenStephen J ChapmanTara C MillsAmit SrivastavaAleksey RudkoMaxim B FreidinValery P PuzyrevShafat AliShweta AggarwalRupali ChopraBelum S N ReddyVijay K GargSuchismita RoySarah MeisnerSunil K HazraBibhuti SahaSian FloydBrendan J KeatingCecilia KimBenjamin P FairfaxJulian C KnightPhilip C HillRichard A AdegbolaHakon HakonarsonPaul E M FineRamasamy M PitchappanRameshwar N K BamezaiAdrian V S HillFredrik O VannbergPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 6, p e1000979 (2010) |
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DOAJ |
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DOAJ |
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Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 |
| spellingShingle |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Sunny H Wong Sailesh Gochhait Dheeraj Malhotra Fredrik H Pettersson Yik Y Teo Chiea C Khor Anna Rautanen Stephen J Chapman Tara C Mills Amit Srivastava Aleksey Rudko Maxim B Freidin Valery P Puzyrev Shafat Ali Shweta Aggarwal Rupali Chopra Belum S N Reddy Vijay K Garg Suchismita Roy Sarah Meisner Sunil K Hazra Bibhuti Saha Sian Floyd Brendan J Keating Cecilia Kim Benjamin P Fairfax Julian C Knight Philip C Hill Richard A Adegbola Hakon Hakonarson Paul E M Fine Ramasamy M Pitchappan Rameshwar N K Bamezai Adrian V S Hill Fredrik O Vannberg Leprosy and the adaptation of human toll-like receptor 1. |
| description |
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. |
| format |
article |
| author |
Sunny H Wong Sailesh Gochhait Dheeraj Malhotra Fredrik H Pettersson Yik Y Teo Chiea C Khor Anna Rautanen Stephen J Chapman Tara C Mills Amit Srivastava Aleksey Rudko Maxim B Freidin Valery P Puzyrev Shafat Ali Shweta Aggarwal Rupali Chopra Belum S N Reddy Vijay K Garg Suchismita Roy Sarah Meisner Sunil K Hazra Bibhuti Saha Sian Floyd Brendan J Keating Cecilia Kim Benjamin P Fairfax Julian C Knight Philip C Hill Richard A Adegbola Hakon Hakonarson Paul E M Fine Ramasamy M Pitchappan Rameshwar N K Bamezai Adrian V S Hill Fredrik O Vannberg |
| author_facet |
Sunny H Wong Sailesh Gochhait Dheeraj Malhotra Fredrik H Pettersson Yik Y Teo Chiea C Khor Anna Rautanen Stephen J Chapman Tara C Mills Amit Srivastava Aleksey Rudko Maxim B Freidin Valery P Puzyrev Shafat Ali Shweta Aggarwal Rupali Chopra Belum S N Reddy Vijay K Garg Suchismita Roy Sarah Meisner Sunil K Hazra Bibhuti Saha Sian Floyd Brendan J Keating Cecilia Kim Benjamin P Fairfax Julian C Knight Philip C Hill Richard A Adegbola Hakon Hakonarson Paul E M Fine Ramasamy M Pitchappan Rameshwar N K Bamezai Adrian V S Hill Fredrik O Vannberg |
| author_sort |
Sunny H Wong |
| title |
Leprosy and the adaptation of human toll-like receptor 1. |
| title_short |
Leprosy and the adaptation of human toll-like receptor 1. |
| title_full |
Leprosy and the adaptation of human toll-like receptor 1. |
| title_fullStr |
Leprosy and the adaptation of human toll-like receptor 1. |
| title_full_unstemmed |
Leprosy and the adaptation of human toll-like receptor 1. |
| title_sort |
leprosy and the adaptation of human toll-like receptor 1. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2010 |
| url |
https://doaj.org/article/64063bfbf0014cd68c02a3a26d68c81c |
| work_keys_str_mv |
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