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

Fakiola, Michaela, Strange, Amy, Cordell, Heather J., Miller, E. Nancy, Pirinen, Matti, Su, Zhan, Mishra, Anshuman, Mehrotra, Sanjana, Monteiro, Gloria R., Band, Gavin, Bellenguez, Celine, Dronov, Serge, Edkins, Sarah, Freeman, Colin, Giannoulatou, Eleni, Gray, Emma, Hunt, Sarah E., Lacerda, Henio G., Langford, Cordelia, Pearson, Richard, Pontes, Nubia N., Rai, Madhukar, Singh, Shri P., Smith, Linda, Sousa, Olivia, Vukcevic, Damjan, Bramon, Elvira, Brown, Matthew A., Casas, Juan P., Corvin, Aiden, Duncanson, Audrey, Jankowski, Janusz, Markus, Hugh S., Mathew, Christopher G., Palmer, Colin N. A., Plomin, Robert, Rautanen, Anna, Sawcer, Stephen J., Trembath, Richard C., Viswanathan, Ananth C., Wood, Nicholas W., Wilson, Mary E., Deloukas, Panos, Peltonen, Leena, Christiansen, Frank, Witt, Campbell, Jeronimo, Selma M. B., Sundar, Shyam, Spencer, Chris C. A., Blackwell, Jenefer M., Donnelly, Peter, LeishGEN Consortium and Wellcome Trust Case Control Consortium 2 (2013) Common variants in the HLA-DRB1-HLA-DQA1 HLA class II region are associated with susceptibility to visceral leishmaniasis. Nature Genetics, 45 2: 208-213. doi:10.1038/ng.2518

Author Fakiola, Michaela
Strange, Amy
Cordell, Heather J.
Miller, E. Nancy
Pirinen, Matti
Su, Zhan
Mishra, Anshuman
Mehrotra, Sanjana
Monteiro, Gloria R.
Band, Gavin
Bellenguez, Celine
Dronov, Serge
Edkins, Sarah
Freeman, Colin
Giannoulatou, Eleni
Gray, Emma
Hunt, Sarah E.
Lacerda, Henio G.
Langford, Cordelia
Pearson, Richard
Pontes, Nubia N.
Rai, Madhukar
Singh, Shri P.
Smith, Linda
Sousa, Olivia
Vukcevic, Damjan
Bramon, Elvira
Brown, Matthew A.
Casas, Juan P.
Corvin, Aiden
Duncanson, Audrey
Jankowski, Janusz
Markus, Hugh S.
Mathew, Christopher G.
Palmer, Colin N. A.
Plomin, Robert
Rautanen, Anna
Sawcer, Stephen J.
Trembath, Richard C.
Viswanathan, Ananth C.
Wood, Nicholas W.
Wilson, Mary E.
Deloukas, Panos
Peltonen, Leena
Christiansen, Frank
Witt, Campbell
Jeronimo, Selma M. B.
Sundar, Shyam
Spencer, Chris C. A.
Blackwell, Jenefer M.
Donnelly, Peter
LeishGEN Consortium
Wellcome Trust Case Control Consortium 2
Title Common variants in the HLA-DRB1-HLA-DQA1 HLA class II region are associated with susceptibility to visceral leishmaniasis
Journal name Nature Genetics   Check publisher's open access policy
ISSN 1061-4036
Publication date 2013-02-01
Year available 2013
Sub-type Article (original research)
DOI 10.1038/ng.2518
Open Access Status Not Open Access
Volume 45
Issue 2
Start page 208
End page 213
Total pages 6
Place of publication New York, NY., United States
Publisher Nature Publishing Group
Language eng
Subject 1311 Genetics
Abstract Pancreatitis occurs in approximately 4% of patients treated with the thiopurines azathioprine or mercaptopurine. Its development is unpredictable and almost always leads to drug withdrawal. We identified patients with inflammatory bowel disease (IBD) who had developed pancreatitis within 3 months of starting these drugs from 168 sites around the world. After detailed case adjudication, we performed a genome-wide association study on 172 cases and 2,035 controls with IBD. We identified strong evidence of association within the class II HLA region, with the most significant association identified at rs2647087 (odds ratio 2.59, 95% confidence interval 2.07-3.26, P = 2 × 10(-16)). We replicated these findings in an independent set of 78 cases and 472 controls with IBD matched for drug exposure. Fine mapping of the HLA region identified association with the HLA-DQA1*02:01-HLA-DRB1*07:01 haplotype. Patients heterozygous at rs2647087 have a 9% risk of developing pancreatitis after administration of a thiopurine, whereas homozygotes have a 17% risk.
Formatted abstract
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 × 10 -17 and odds ratio (OR) = 1.41, 95% confidence interval (CI) = 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.
Keyword Genome wide association
Infectious Diseases
Northeastern Brazil
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID WT097835MF
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
UQ Diamantina Institute Publications
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Citation counts: TR Web of Science Citation Count  Cited 41 times in Thomson Reuters Web of Science Article | Citations
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