Variation at HLA-DRB1 is associated with resistance to enteric fever.
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 C(1). 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.
1] Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam. [2] Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, Oxford University, Oxford, UK. [3] Nossal Institute of Global Health, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
Sarah J
000000017873933X
SJ
Dunstan
1] Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam. [2] Faculty of Biology, University of Science, Vietnam National University, Ho Chi Minh City, Vietnam.
Nguyen Thi
NT
Hue
1] Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea. [2] Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. [3] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA. [4] Partners Center for Personalized Genetic Medicine, Boston, Massachusetts, USA.
Buhm
B
Han
Genome Institute of Singapore, Singapore.
Zheng
Z
Li
Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
Trinh Thi Bich
TT
Tram
Genome Institute of Singapore, Singapore.
Kar Seng
0000000238227759
KS
Sim
1] Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam. [2] Liverpool School of Tropical Medicine, Liverpool, UK.
Christopher M
CM
Parry
Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
Nguyen Tran
NT
Chinh
Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
Ha
H
Vinh
Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
Nguyen Phu Huong
NP
Lan
Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
Nga Tran Vu
NT
Thieu
Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
Phat Voong
PV
Vinh
Oxford University Clinical Research Unit-Nepal, Patan Academy of Health Sciences, Patan Hospital, Patan, Nepal.
Samir
S
Koirala
Oxford University Clinical Research Unit-Nepal, Patan Academy of Health Sciences, Patan Hospital, Patan, Nepal.
Sabina
S
Dongol
Oxford University Clinical Research Unit-Nepal, Patan Academy of Health Sciences, Patan Hospital, Patan, Nepal.
Amit
A
Arjyal
Oxford University Clinical Research Unit-Nepal, Patan Academy of Health Sciences, Patan Hospital, Patan, Nepal.
Abhilasha
A
Karkey
Oxford University Clinical Research Unit-Nepal, Patan Academy of Health Sciences, Patan Hospital, Patan, Nepal.
Olita
O
Shilpakar
1] Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam. [2] Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, Oxford University, Oxford, UK.
Christiane
C
Dolecek
Genome Institute of Singapore, Singapore.
Jia Nee
0000000198992308
JN
Foo
Dong Thap Provincial Hospital, Cao Lanh, Vietnam.
Le Thi
le T
Phuong
Dong Thap Provincial Hospital, Cao Lanh, Vietnam.
Mai Ngoc
MN
Lanh
Vietnam National Institute of Ophthalmology, Hanoi, Vietnam.
Tan
T
Do
Singapore Eye Research Institute, Singapore.
Tin
T
Aung
Vietnam National Institute of Ophthalmology, Hanoi, Vietnam.
Do Nu
DN
Hon
1] Department of Statistics and Applied Probability, National University of Singapore, Singapore. [2] Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
Yik Ying
YY
Teo
1] Genome Institute of Singapore, Singapore. [2] London School of Tropical Medicine and Hygiene, London, UK.
Martin L
ML
Hibberd
1] Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam. [2] Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, Oxford University, Oxford, UK.
Katherine L
KL
Anders
1] Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. [2] Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Yukinori
Y
Okada
1] Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. [2] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA. [3] Partners Center for Personalized Genetic Medicine, Boston, Massachusetts, USA. [4] Department of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, USA. [5] Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.
Soumya
S
Raychaudhuri
1] Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam. [2] Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, Oxford University, Oxford, UK. [3] Department of Microbiology and Immunology, The University of Melbourne, Melbourne, Victoria, Australia.
Cameron P
CP
Simmons
1] Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam. [2] Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, Oxford University, Oxford, UK. [3] London School of Tropical Medicine and Hygiene, London, UK.
Stephen
S
Baker
1] Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands. [2] Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
Paul I W
PI
de Bakker
Oxford University Clinical Research Unit-Nepal, Patan Academy of Health Sciences, Patan Hospital, Patan, Nepal.
Buddha
B
Basnyat
Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
Tran Tinh
TT
Hien
1] Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam. [2] Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, Oxford University, Oxford, UK.
Jeremy J
JJ
Farrar
1] Genome Institute of Singapore, Singapore. [2] Singapore Eye Research Institute, Singapore. [3] Saw Swee Hock School of Public Health, National University of Singapore, Singapore. [4] Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. [5] Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Chiea Chuen
CC
Khor
D000483:Alleles; D017951:Antigen Presentation; D015415:Biomarkers; D002874:Chromosome Mapping; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005838:Genotype; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006801:Humans; D015233:Models, Statistical; D009390:Nepal; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D025341:Principal Component Analysis; D012044:Regression Analysis; D014435:Typhoid Fever / Q000235:genetics*; D014744:Vietnam
D015415:Biomarkers; D005819:Genetic Markers; D059811:HLA-DRB1 Chains; C527195:HLA-DRB1*04 antigen