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

LeishGEN Consortium,
Wellcome Trust Case Control Consortium 2,
Michaela Fakiola,^{1, 29}
Amy Strange,^{2, 29}
Heather J Cordell,³
E Nancy Miller,^{1, 28}
Matti Pirinen,²
Zhan Su,²
Anshuman Mishra,⁴
Sanjana Mehrotra,⁴
Gloria R Monteiro,⁵
Gavin Band,²
Céline Bellenguez,²
Serge Dronov,⁶
Sarah Edkins,⁶
Colin Freeman,²
Eleni Giannoulatou,²
Emma Gray,⁶
Sarah E Hunt,⁶
Henio G Lacerda,⁷
Cordelia Langford,⁶
Richard Pearson,²
Núbia N Pontes,⁵
Madhukar Rai,⁴
Shri P Singh,⁴
Linda Smith,⁸
Olivia Sousa,⁵
Damjan Vukcevic,²
Elvira Bramon,⁹
Matthew A Brown,¹⁰
Juan P Casas,¹¹
Aiden Corvin,¹²
Audrey Duncanson,¹³
Janusz Jankowski,¹⁴
Hugh S Markus,¹⁵
Christopher G Mathew,¹⁶
Colin N A Palmer,¹⁷
Robert Plomin,¹⁸
Anna Rautanen,²
Stephen J Sawcer,¹⁹
Richard C Trembath,²⁰
Ananth C Viswanathan,^{21, 22}
Nicholas W Wood,²³
Mary E Wilson,^{24, 25}
Panos Deloukas,⁶
Leena Peltonen,^{6, 28}
Frank Christiansen,⁸
Campbell Witt,⁸
Selma M B Jeronimo,⁵
Shyam Sundar,⁴
Chris C A Spencer,²
Jenefer M Blackwell^{1, 26, 30}
& Peter Donnelly^{2, 27, 30}
et al.

Journal name:: Nature Genetics
Year published:: (2013)
DOI:: doi:10.1038/ng.2518

Received: 23 August 2012
Accepted: 06 December 2012
Published online: 06 January 2013

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.

At a glance

Figures

left

Figure 1: Plot of genome-wide association results for the separate and combined discovery GWAS using a variance components method.

SNPs in red show regions with replicated association to visceral leishmaniasis susceptibility. (a) Indian discovery data at 526,731 SNPs. (b) Brazilian discovery data at 553,323 SNPs. (c) Plot of the meta-analysis genome-wide association results.
Figure 2: Regional association plots of the signal at the MHC region.

(a–c) Results are shown for the Indian discovery (a), Brazilian discovery (b) and meta-analysis of the discovery cohorts (c). Top, −log₁₀ P values. SNPs are colored on the basis of their LD with the labeled hit SNP, as calculated in the Indian controls (a) and Brazilian founders (b); no coloring is shown for the meta-analysis (c). The SNP colored in green is the hit SNP in the Brazilian cohort (a), Indian cohort (b) and Indian and Brazilian cohorts (c). Bottom, fine-scale recombination rates estimated from CEU HapMap population with genes marked as horizontal blue arrows. Genes flanking the hit SNP are colored red and are labeled.
Figure 3: Schematic of the HLA and SNP phased Indian discovery haplotypes in the MHC region.