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Variation at HLA-DRB1 is associated with resistance to enteric fever

2014; Nature Portfolio; Volume: 46; Issue: 12 Linguagem: Inglês

10.1038/ng.3143

1546-1718

Sarah J. Dunstan, Hue Thi Nguyen, Buhm Han, Zheng Li, Trinh Thi Bich Tram, Kar Seng Sim, Christopher M. Parry, Nguyen Tran Chinh, Ha Vinh, Nguyen Phu Huong Lan, Nga Tran Vu Thieu, Phat Voong Vinh, Samir Koirala, Sabina Dongol, Amit Arjyal, Abhilasha Karkey, Olita Shilpakar, Christiane Dolecek, Jia Nee Foo, Lê Thị Phượng, Mai Ngoc Lanh, Tan Do, Tin Aung, Do Nu Hon, Yik Ying Teo, Martin L. Hibberd, Katherine L. Anders, Yukinori Okada, Soumya Raychaudhuri, Cameron P. Simmons, Stephen Baker, Paul I. W. de Bakker, Buddha Basnyat, Tran Tinh Hien, Jeremy Farrar, Chiea Chuen Khor,

Hepatitis B Virus Studies

Sarah Dunstan, Chiea Chuen Khor and colleagues identify common variants in the HLA-DRB1 region associated with resistance to enteric fever. Individuals carrying the protective variants exhibit roughly five-fold higher resistance against developing this life-threatening infectious disease. Enteric fever affects more than 25 million people annually and results from systemic infection with Salmonella enterica serovar Typhi or Paratyphi pathovars A, B or C1. We conducted a genome-wide association study of 432 individuals with blood culture–confirmed enteric fever and 2,011 controls from Vietnam. We observed strong association at rs7765379 (odds ratio (OR) for the minor allele = 0.18, P = 4.5 × 10−10), a marker mapping to the HLA class II region, in proximity to HLA-DQB1 and HLA-DRB1. We replicated this association in 595 enteric fever cases and 386 controls from Nepal and also in a second independent collection of 151 cases and 668 controls from Vietnam. Imputation-based fine-mapping across the extended MHC region showed that the classical HLA-DRB1*04:05 allele (OR = 0.14, P = 2.60 × 10−11) could entirely explain the association at rs7765379, thus implicating HLA-DRB1 as a major contributor to resistance against enteric fever, presumably through antigen presentation.