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

• Published in: Nature genetics Vol. 45; no. 2; pp. 208 - 213
• Main Authors: Fakiola, Michaela, Strange, Amy, Cordell, Heather J, Miller, E Nancy, Pirinen, Matti, Su, Zhan, Mishra, Anshuman, Mehrotra, Sanjana, Monteiro, Gloria R, Band, Gavin, Bellenguez, Céline, Dronov, Serge, Edkins, Sarah, Freeman, Colin, Giannoulatou, Eleni, Gray, Emma, Hunt, Sarah E, Lacerda, Henio G, Langford, Cordelia, Pearson, Richard, Pontes, Núbia 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
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2013; Nature Publishing Group
• Subjects: 631/208/205/2138; 631/208/457/649; 631/208/727/2000; 692/699/255/1715; Agriculture; Animal Genetics and Genomics; Biomedicine; Brazil; Cancer Research; Disease; Disease susceptibility; Electrophoresis, Agar Gel; Gene Frequency; Gene Function; Genetic aspects; Genetic Predisposition to Disease - genetics; Genetics; Genome-Wide Association Study; Genotype; Geography; Haplotypes; Haplotypes - genetics; Health aspects; HLA-DQ alpha-Chains - genetics; HLA-DRB1 Chains - genetics; Human Genetics; Humans; Identification and classification; India; Kala-azar; Leishmaniasis, Visceral - genetics; letter; Linear Models; Methods; Odds Ratio; Oligonucleotide Array Sequence Analysis; Parasites; Parasitic diseases; Polymorphism, Single Nucleotide - genetics; Quality control; Quantitative trait loci; Risk factors; Studies; Tropical diseases; Vector-borne diseases; Brazil; India
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.2518

Jenefer Blackwell, Peter Donnelly and colleagues report a genome-wide association study for visceral leishmaniasis using studies from India and Brazil, with replication in an additional Indian study. They identify common variants at the HLA-DRB1 – HLA-DQA1 HLA class II region associated with susceptibility to visceral leishmaniasis. 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.