Common variants in the HLA-DRB1-HLA-DQA1 HLA class II region are associated with susceptibility to visceral leishmaniasis

被引：78

作者：

Fakiola, Michaela ^{[1
]}

Strange, Amy

Cordell, Heather J. ^{[3
]}

Miller, E. Nancy ^{[1
]}

Pirinen, Matti ^{[2
]}

Su, Zhan ^{[2
]}

Mishra, Anshuman ^{[4
]}

Mehrotra, Sanjana ^{[4
]}

Monteiro, Gloria R. ^{[5
]}

Band, Gavin ^{[2
]}

Bellenguez, Celine ^{[2
]}

Dronov, Serge ^{[6
]}

Edkins, Sarah ^{[6
]}

Freeman, Colin ^{[2
]}

Giannoulatou, Eleni ^{[2
]}

Gray, Emma ^{[6
]}

Hunt, Sarah E. ^{[6
]}

Lacerda, Henio G. ^{[7
]}

Langford, Cordelia ^{[6
]}

Pearson, Richard ^{[2
]}

Pontes, Nubia N. ^{[5
]}

Rai, Madhukar ^{[4
]}

Singh, Shri P. ^{[4
]}

Smith, Linda ^{[8
]}

Sousa, Olivia ^{[5
]}

Vukcevic, Damjan ^{[2
]}

Bramon, Elvira ^{[9
,10
]}

Brown, Matthew A. ^{[11
]}

Casas, Juan P. ^{[12
]}

Corvin, Aiden ^{[13
]}

Duncanson, Audrey ^{[14
]}

Jankowski, Janusz ^{[15
]}

Markus, Hugh S. ^{[16
]}

Mathew, Christopher G. ^{[17
]}

Palmer, Colin N. A. ^{[18
]}

Plomin, Robert ^{[19
]}

Rautanen, Anna ^{[2
]}

Sawcer, Stephen J. ^{[20
]}

Trembath, Richard C. ^{[21
]}

Viswanathan, Ananth C. ^{[22
,23
]}

Wood, Nicholas W. ^{[24
]}

Wilson, Mary E. ^{[25
,26
]}

Deloukas, Panos ^{[6
]}

Peltonen, Leena ^{[6
]}

Christiansen, Frank ^{[8
]}

Witt, Campbell ^{[8
]}

Jeronimo, Selma M. B. ^{[5
]}

Sundar, Shyam ^{[4
]}

Spencer, Chris C. A. ^{[2
]}

Blackwell, Jenefer M. ^{[1
,27
]}

机构：

[1] Univ Cambridge, Addenbrookes Hosp, Cambridge Inst Med Res, Sch Clin Med, Cambridge CB2 2QQ, England

[2] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[3] Newcastle Univ, Inst Genet Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England

[4] Banaras Hindu Univ, Inst Med Sci, Varanasi 221005, Uttar Pradesh, India

[5] Univ Fed Rio Grande do Norte, Dept Biochem, Ctr Biosci, BR-59072970 Natal, RN, Brazil

[6] Wellcome Trust Sanger Inst, Cambridge, England

[7] Univ Fed Rio Grande do Norte, Dept Infect Dis, BR-59072970 Natal, RN, Brazil

[8] Royal Perth Hosp, Dept Clin Immunol, Perth, WA 6001, Australia

[9] S London & Maudsley Natl Hlth Serv NHS Fdn Trust, Natl Inst Hlth Res NIHR Biomed Res Ctr Mental Hlt, London, England

[10] Kings Coll London, Inst Psychiat, London WC2R 2LS, England

[11] Univ Queensland, Diamantina Inst, Princess Alexandra Hosp, Brisbane, Qld, Australia

[12] London Sch Hyg & Trop Med, Dept Epidemiol & Populat Hlth, London WC1, England

[13] Trinity Coll Dublin, Neuropsychiat Genet Res Grp, Inst Mol Med, Dublin, Ireland

[14] Wellcome Trust Res Labs, London, England

[15] Univ Oxford, Dept Oncol, Oxford, England

[16] St Georges Univ London, Stroke & Dementia Res Grp, London, England

[17] Kings Coll London, Sch Med, Dept Med & Mol Genet, Guys Hosp, London WC2R 2LS, England

[18] Univ Dundee, Ninewells Hosp & Med Sch, Med Res Inst, Dundee DD1 9SY, Scotland

[19] Kings Coll London, Inst Psychiat, Social Genet & Dev Psychiat Ctr, London WC2R 2LS, England

[20] Univ Cambridge, Addenbrookes Hosp, Dept Clin Neurosci, Cambridge CB2 2QQ, England

[21] Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab ICDEM, Oxford OX3 7LJ, England

[22] Moorfields Eye Hosp NHS Fdn Trust, NIHR Biomed Ctr Ophthalmol, London, England

[23] UCL, Inst Ophthalmol, London, England

[24] Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England

[25] Univ Iowa, Dept Internal Med, Iowa City, IA 52242 USA

[26] Vet Affairs VA Med Ctr, Iowa City, IA USA

[27] Univ Western Australia, Telethon Inst Child Hlth Res, Ctr Child Hlth Res, Subiaco, WA, Australia

[28] Univ Oxford, Dept Stat, Oxford OX1 3TG, England

来源：

NATURE GENETICS | 2013年 / 45卷 / 02期

基金：

英国惠康基金; 美国国家卫生研究院;

关键词：

GENOME-WIDE ASSOCIATION; INFECTION; POLYMORPHISM; CHAGASI; GENES; MODEL;

D O I：

10.1038/ng.2518

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

To identify susceptibility loci for visceral leishmaniasis, we undertook genome-wide association studies in two populations: 989 cases and 1,089 controls from India and 357 cases in 308 Brazilian families (1,970 individuals). The HLA-DRB1-HLA-DQA1 locus was the only region to show strong evidence of association in both populations. Replication at this region was undertaken in a second Indian population comprising 941 cases and 990 controls, and combined analysis across the three cohorts for rs9271858 at this locus showed P-combined = 2.76 x 10(-17) and odds ratio (OR) = 1.41, 95% confidence interval (Cl) = 1.30-1.52. A conditional analysis provided evidence for multiple associations within the HLA-DRB1-HLA-DQA1 region, and a model in which risk differed between three groups of haplotypes better explained the signal and was significant in the Indian discovery and replication cohorts. In conclusion, the HLA-DRB1-HLA-DQA1 HLA class II region contributes to visceral leishmaniasis susceptibility in India and Brazil, suggesting shared genetic risk factors for visceral leishmaniasis that cross the epidemiological divides of geography and parasite species.

引用

页码：208 / 213

页数：6

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