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

Michaela Fakiola; Amy Strange; Heather J Cordell; E Nancy Miller; Matti Pirinen; Zhan Su; Anshuman Mishra; Sanjana Mehrotra; Gloria R Monteiro; Gavin Band; Céline Bellenguez; Serge Dronov; Sarah Edkins; Colin Freeman; Eleni Giannoulatou; Emma Gray; Sarah E Hunt; Henio G Lacerda; Cordelia Langford; Richard Pearson; Núbia N Pontes; Madhukar Rai; Shri P Singh; Linda Smith; Olivia Sousa; Damjan Vukcevic; Elvira Bramon-Bosch; Matthew A Brown; Juan P Casas; Aiden Corvin; Audrey Duncanson; Janusz Jankowski; Hugh S Markus; Christopher Mathew; Colin N A Palmer; Robert Plomin; Anna Rautanen; Stephen J Sawcer; Richard C. Trembath; Ananth C Viswanathan; Nicholas W Wood; Mary E Wilson; Panos Deloukas; Leena Peltonen; Frank Christiansen; Campbell Witt; Selma M B Jeronimo; Shyam Sundar; Chris C A Spencer; Jenefer M Blackwell; LeishGEN Consortium

doi:10.1038/ng.2518

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

Michaela Fakiola, Amy Strange, Heather J Cordell, E Nancy Miller, Matti Pirinen, Zhan Su, Anshuman Mishra, Sanjana Mehrotra, Gloria R Monteiro, Gavin Band, Céline Bellenguez, Serge Dronov, Sarah Edkins, Colin Freeman, Eleni Giannoulatou, Emma Gray, Sarah E Hunt, Henio G Lacerda, Cordelia Langford, Richard PearsonNúbia N Pontes, Madhukar Rai, Shri P Singh, Linda Smith, Olivia Sousa, Damjan Vukcevic, Elvira Bramon-Bosch, Matthew A Brown, Juan P Casas, Aiden Corvin, Audrey Duncanson, Janusz Jankowski, Hugh S Markus, Christopher Mathew, Colin N A Palmer, Robert Plomin, Anna Rautanen, Stephen J Sawcer, Richard C. Trembath, Ananth C Viswanathan, Nicholas W Wood, Mary E Wilson, Panos Deloukas, Leena Peltonen, Frank Christiansen, Campbell Witt, Selma M B Jeronimo, Shyam Sundar, Chris C A Spencer, Jenefer M Blackwell, LeishGEN Consortium

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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.

Original language	English
Pages (from-to)	208-213
Number of pages	6
Journal	Nature Genetics
Volume	45
Issue number	2
DOIs	https://doi.org/10.1038/ng.2518
Publication status	Published - 1 Feb 2013

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Common variants in the HLA-DRB1-HLA_FAKIOLA Accepted 6Dec2012 GREEN AAMAccepted author manuscript, 1.32 MB

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3664012/

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Fakiola, M., Strange, A., Cordell, H. J., Miller, E. N., Pirinen, M., Su, Z., Mishra, A., Mehrotra, S., Monteiro, G. R., Band, G., Bellenguez, C., Dronov, S., Edkins, S., Freeman, C., Giannoulatou, E., Gray, E., Hunt, S. E., Lacerda, H. G., Langford, C., ... LeishGEN Consortium (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. https://doi.org/10.1038/ng.2518

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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.",

author = "Michaela Fakiola and Amy Strange and Cordell, {Heather J} and Miller, {E Nancy} and Matti Pirinen and Zhan Su and Anshuman Mishra and Sanjana Mehrotra and Monteiro, {Gloria R} and Gavin Band and C{\'e}line Bellenguez and Serge Dronov and Sarah Edkins and Colin Freeman and Eleni Giannoulatou and Emma Gray and Hunt, {Sarah E} and Lacerda, {Henio G} and Cordelia Langford and Richard Pearson and Pontes, {N{\'u}bia N} and Madhukar Rai and Singh, {Shri P} and Linda Smith and Olivia Sousa and Damjan Vukcevic and Elvira Bramon-Bosch and Brown, {Matthew A} and Casas, {Juan P} and Aiden Corvin and Audrey Duncanson and Janusz Jankowski and Markus, {Hugh S} and Christopher Mathew and Palmer, {Colin N A} and Robert Plomin and Anna Rautanen and Sawcer, {Stephen J} and Trembath, {Richard C.} and Viswanathan, {Ananth C} and Wood, {Nicholas W} and Wilson, {Mary E} and Panos Deloukas and Leena Peltonen and Frank Christiansen and Campbell Witt and Jeronimo, {Selma M B} and Shyam Sundar and Spencer, {Chris C A} and Blackwell, {Jenefer M} and {LeishGEN Consortium}",

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Fakiola, M, Strange, A, Cordell, HJ, Miller, EN, Pirinen, M, Su, Z, Mishra, A, Mehrotra, S, Monteiro, GR, Band, G, Bellenguez, C, Dronov, S, Edkins, S, Freeman, C, Giannoulatou, E, Gray, E, Hunt, SE, Lacerda, HG, Langford, C, Pearson, R, Pontes, NN, Rai, M, Singh, SP, Smith, L, Sousa, O, Vukcevic, D, Bramon-Bosch, E, Brown, MA, Casas, JP, Corvin, A, Duncanson, A, Jankowski, J, Markus, HS, Mathew, C, Palmer, CNA, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Viswanathan, AC, Wood, NW, Wilson, ME, Deloukas, P, Peltonen, L, Christiansen, F, Witt, C, Jeronimo, SMB, Sundar, S, Spencer, CCA, Blackwell, JM & LeishGEN Consortium 2013, 'Common variants in the HLA-DRB1-HLA-DQA1 HLA class II region are associated with susceptibility to visceral leishmaniasis', Nature Genetics, vol. 45, no. 2, pp. 208-213. https://doi.org/10.1038/ng.2518

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T1 - Common variants in the HLA-DRB1-HLA-DQA1 HLA class II region are associated with susceptibility to visceral leishmaniasis

AU - Fakiola, Michaela

AU - Strange, Amy

AU - Cordell, Heather J

AU - Miller, E Nancy

AU - Pirinen, Matti

AU - Su, Zhan

AU - Mishra, Anshuman

AU - Mehrotra, Sanjana

AU - Monteiro, Gloria R

AU - Band, Gavin

AU - Bellenguez, Céline

AU - Dronov, Serge

AU - Edkins, Sarah

AU - Freeman, Colin

AU - Giannoulatou, Eleni

AU - Gray, Emma

AU - Hunt, Sarah E

AU - Lacerda, Henio G

AU - Langford, Cordelia

AU - Pearson, Richard

AU - Pontes, Núbia N

AU - Rai, Madhukar

AU - Singh, Shri P

AU - Smith, Linda

AU - Sousa, Olivia

AU - Vukcevic, Damjan

AU - Bramon-Bosch, Elvira

AU - Brown, Matthew A

AU - Casas, Juan P

AU - Corvin, Aiden

AU - Duncanson, Audrey

AU - Jankowski, Janusz

AU - Markus, Hugh S

AU - Mathew, Christopher

AU - Palmer, Colin N A

AU - Plomin, Robert

AU - Rautanen, Anna

AU - Sawcer, Stephen J

AU - Trembath, Richard C.

AU - Viswanathan, Ananth C

AU - Wood, Nicholas W

AU - Wilson, Mary E

AU - Deloukas, Panos

AU - Peltonen, Leena

AU - Christiansen, Frank

AU - Witt, Campbell

AU - Jeronimo, Selma M B

AU - Sundar, Shyam

AU - Spencer, Chris C A

AU - Blackwell, Jenefer M

AU - LeishGEN Consortium

N1 - This article is not freely accessible but you may have access through your institution.

PY - 2013/2/1

Y1 - 2013/2/1

N2 - 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.

AB - 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.

U2 - 10.1038/ng.2518

DO - 10.1038/ng.2518

M3 - Letter

C2 - 23291585

SN - 1061-4036

VL - 45

SP - 208

EP - 213

JO - Nature Genetics

JF - Nature Genetics

IS - 2

ER -

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

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