Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Association results for enteric fever within the broad HLA region.

Similar content being viewed by others

Accession codes

Accessions

NCBI Reference Sequence

References

  1. Buckle, G.C., Walker, C.L. & Black, R.E. Typhoid fever and paratyphoid fever: systematic review to estimate global morbidity and mortality for 2010. J. Glob. Health 2, 010401 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Crump, J.A., Luby, S.P. & Mintz, E.D. The global burden of typhoid fever. Bull. World Health Organ. 82, 346–353 (2004).

    PubMed  PubMed Central  Google Scholar 

  3. Cvjetanović, B., Grab, B. & Uemura, K. Epidemiological model of typhoid fever and its use in the planning and evaluation of antityphoid immunization and sanitation programmes. Bull. World Health Organ. 45, 53–75 (1971).

    PubMed  PubMed Central  Google Scholar 

  4. Crump, J.A. & Mintz, E.D. Global trends in typhoid and paratyphoid fever. Clin. Infect. Dis. 50, 241–246 (2010).

    Article  PubMed  Google Scholar 

  5. McGregor, A.C., Waddington, C.S. & Pollard, A.J. Prospects for prevention of Salmonella infection in children through vaccination. Curr. Opin. Infect. Dis. 26, 254–262 (2013).

    Article  PubMed  Google Scholar 

  6. Karki, S., Shakya, P., Cheng, A.C., Dumre, S.P. & Leder, K. Trends of etiology and drug resistance in enteric fever in the last two decades in Nepal: a systematic review and meta-analysis. Clin. Infect. Dis. 57, e167–e176 (2013).

    Article  CAS  PubMed  Google Scholar 

  7. Kingsley, R.A. et al. Genome and transcriptome adaptation accompanying emergence of the definitive type 2 host-restricted Salmonella enterica serovar Typhimurium pathovar. MBio 4, e00565–13 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Wong, V.K. et al. Characterization of the yehUT two-component regulatory system of Salmonella enterica serovar Typhi and Typhimurium. PLoS ONE 8, e84567 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. de Jong, R. et al. Severe mycobacterial and Salmonella infections in interleukin-12 receptor–deficient patients. Science 280, 1435–1438 (1998).

    Article  CAS  PubMed  Google Scholar 

  10. Dunstan, S.J. et al. Typhoid fever and genetic polymorphisms at the natural resistance–associated macrophage protein 1. J. Infect. Dis. 183, 1156–1160 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Dunstan, S.J. et al. Genes of the class II and class III major histocompatibility complex are associated with typhoid fever in Vietnam. J. Infect. Dis. 183, 261–268 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. Dunstan, S.J. et al. A TNF region haplotype offers protection from typhoid fever in Vietnamese patients. Hum. Genet. 122, 51–61 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Dharmana, E. et al. HLA-DRB1*12 is associated with protection against complicated typhoid fever, independent of tumour necrosis factor α. Eur. J. Immunogenet. 29, 297–300 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Fakiola, M. et al. Common variants in the HLA-DRB1HLA-DQA1 HLA class II region are associated with susceptibility to visceral leishmaniasis. Nat. Genet. 45, 208–213 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Huyghe, J.R. et al. Exome array analysis identifies new loci and low-frequency variants influencing insulin processing and secretion. Nat. Genet. 45, 197–201 (2013).

    Article  CAS  PubMed  Google Scholar 

  16. Helgason, A. et al. Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution. Nat. Genet. 39, 218–225 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Pereyra, F. et al. The major genetic determinants of HIV-1 control affect HLA class I peptide presentation. Science 330, 1551–1557 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Jia, X. et al. Imputing amino acid polymorphisms in human leukocyte antigens. PLoS ONE 8, e64683 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Pillai, N.E. et al. Predicting HLA alleles from high-resolution SNP data in three Southeast Asian populations. Hum. Mol. Genet. 23, 4443–4451 (2014).

    Article  CAS  PubMed  Google Scholar 

  20. Raychaudhuri, S. et al. Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat. Genet. 44, 291–296 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Gockel, I. et al. Common variants in the HLA-DQ region confer susceptibility to idiopathic achalasia. Nat. Genet. 46, 901–904 (2014).

    Article  CAS  PubMed  Google Scholar 

  22. Okada, Y. et al. Risk for ACPA-positive rheumatoid arthritis is driven by shared HLA amino acid polymorphisms in Asian and European populations. Hum. Mol. Genet. doi:10.1093/hmg/ddu387 (28 July 2014).

  23. Huang, L., Wang, C. & Rosenberg, N.A. The relationship between imputation error and statistical power in genetic association studies in diverse populations. Am. J. Hum. Genet. 85, 692–698 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Jantsch, J., Chikkaballi, D. & Hensel, M. Cellular aspects of immunity to intracellular Salmonella enterica. Immunol. Rev. 240, 185–195 (2011).

    Article  CAS  PubMed  Google Scholar 

  25. Malik-Kale, P. et al. Salmonella—at home in the host cell. Front. Microbiol. 2, 125 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Haraga, A., Ohlson, M.B. & Miller, S.I. Salmonellae interplay with host cells. Nat. Rev. Microbiol. 6, 53–66 (2008).

    Article  CAS  PubMed  Google Scholar 

  27. Cheminay, C., Mohlenbrink, A. & Hensel, M. Intracellular Salmonella inhibit antigen presentation by dendritic cells. J. Immunol. 174, 2892–2899 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. van den Bergh, E.T., Gasem, M.H., Keuter, M. & Dolmans, M.V. Outcome in three groups of patients with typhoid fever in Indonesia between 1948 and 1990. Trop. Med. Int. Health 4, 211–215 (1999).

    Article  CAS  PubMed  Google Scholar 

  29. Khor, C.C. & Hibberd, M.L. Host-pathogen interactions revealed by human genome-wide surveys. Trends Genet. 28, 233–243 (2012).

    Article  CAS  PubMed  Google Scholar 

  30. Freudenberg, J. et al. Genome-wide association study of rheumatoid arthritis in Koreans: population-specific loci as well as overlap with European susceptibility loci. Arthritis Rheum. 63, 884–893 (2011).

    Article  CAS  PubMed  Google Scholar 

  31. Yamazaki, K. et al. A genome-wide association study identifies 2 susceptibility loci for Crohn's disease in a Japanese population. Gastroenterology 144, 781–788 (2013).

    Article  CAS  PubMed  Google Scholar 

  32. Sfriso, P. et al. Infections and autoimmunity: the multifaceted relationship. J. Leukoc. Biol. 87, 385–395 (2010).

    Article  CAS  PubMed  Google Scholar 

  33. Karlsson, E.K., Kwiatkowski, D.P. & Sabeti, P.C. Natural selection and infectious disease in human populations. Nat. Rev. Genet. 15, 379–393 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. de Bakker, P.I. et al. A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC. Nat. Genet. 38, 1166–1172 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. de Bakker, P.I. & Telenti, A. Infectious diseases not immune to genome-wide association. Nat. Genet. 42, 731–732 (2010).

    Article  CAS  PubMed  Google Scholar 

  36. Davila, S. et al. Genome-wide association study identifies variants in the CFH region associated with host susceptibility to meningococcal disease. Nat. Genet. 42, 772–776 (2010).

    Article  CAS  PubMed  Google Scholar 

  37. Thye, T. et al. Common variants at 11p13 are associated with susceptibility to tuberculosis. Nat. Genet. 44, 257–259 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Thye, T. et al. Genome-wide association analyses identifies a susceptibility locus for tuberculosis on chromosome 18q11.2. Nat. Genet. 42, 739–741 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Fellay, J. et al. A whole-genome association study of major determinants for host control of HIV-1. Science 317, 944–947 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Khor, C.C. et al. Genome-wide association study identifies susceptibility loci for dengue shock syndrome at MICB and PLCE1. Nat. Genet. 43, 1139–1141 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Dean, M. et al. Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Science 273, 1856–1862 (1996).

    Article  CAS  PubMed  Google Scholar 

  42. Huang, Y. et al. The role of a mutant CCR5 allele in HIV-1 transmission and disease progression. Nat. Med. 2, 1240–1243 (1996).

    Article  CAS  PubMed  Google Scholar 

  43. Modiano, D. et al. Haemoglobin C protects against clinical Plasmodium falciparum malaria. Nature 414, 305–308 (2001).

    Article  CAS  PubMed  Google Scholar 

  44. Cao, X.T. et al. A comparative study of ofloxacin and cefixime for treatment of typhoid fever in children. The Dong Nai Pediatric Center Typhoid Study Group. Pediatr. Infect. Dis. J. 18, 245–248 (1999).

    Article  CAS  PubMed  Google Scholar 

  45. Chinh, N.T. et al. A randomized controlled comparison of azithromycin and ofloxacin for treatment of multidrug-resistant or nalidixic acid–resistant enteric fever. Antimicrob. Agents Chemother. 44, 1855–1859 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Luxemburger, C. et al. Risk factors for typhoid fever in the Mekong delta, southern Viet Nam: a case-control study. Trans. R. Soc. Trop. Med. Hyg. 95, 19–23 (2001).

    Article  CAS  PubMed  Google Scholar 

  47. Vinh, H. et al. Double blind comparison of ibuprofen and paracetamol for adjunctive treatment of uncomplicated typhoid fever. Pediatr. Infect. Dis. J. 23, 226–230 (2004).

    Article  PubMed  Google Scholar 

  48. House, D. et al. Cytokine release by lipopolysaccharide-stimulated whole blood from patients with typhoid fever. J. Infect. Dis. 186, 240–245 (2002).

    Article  CAS  PubMed  Google Scholar 

  49. Arjyal, A. et al. Gatifloxacin versus chloramphenicol for uncomplicated enteric fever: an open-label, randomised, controlled trial. Lancet Infect. Dis. 11, 445–454 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Pandit, A. et al. An open randomized comparison of gatifloxacin versus cefixime for the treatment of uncomplicated enteric fever. PLoS ONE 2, e542 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Koirala, S. et al. Gatifloxacin versus ofloxacin for the treatment of uncomplicated enteric fever in Nepal: an open-label, randomized, controlled trial. PLoS Negl. Trop. Dis. 7, e2523 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Tall, A.R. CETP inhibitors to increase HDL cholesterol levels. N. Engl. J. Med. 356, 1364–1366 (2007).

    Article  CAS  PubMed  Google Scholar 

  54. 1000 Genomes Project Consortium. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010).

  55. Purcell, S., Cherny, S.S. & Sham, P.C. Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 19, 149–150 (2003).

    Article  CAS  PubMed  Google Scholar 

  56. Purdue, M.P. et al. Genome-wide association study of renal cell carcinoma identifies two susceptibility loci on 2p21 and 11q13.3. Nat. Genet. 43, 60–65 (2011).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the Wellcome Trust, UK as part of their Major Overseas Program in Viet Nam (089276/Z/09/Z) and by the Biomedical Research Council, Agency for Science, Technology and Research, Singapore. S.B. is a Sir Henry Dale Fellow, jointly funded by the Wellcome Trust and the Royal Society (100087/Z/12/Z). P.I.W.d.B. acknowledges support from the Netherlands Organization for Scientific Research (Vernieuwingsimpuls VIDI Award NWO project number 016.126.354).

Author information

Authors and Affiliations

Authors

Contributions

C.C.K. and S.J.D. are the principal investigators for the study who conceived and obtained funding for the project. C.C.K. organized and supervised the GWAS and replication genotyping pipeline, devised the overall analysis plan and wrote the first draft of the manuscript with input from S.J.D. S.J.D. established the enteric fever cohorts for the discovery and replication stages of this genetics study by working with J.J.F., T.T.H., N.P.H.L., N.T.H., T.T.B.T., C.M.P., N.T.C., H.V., L.T.P., M.N.L., N.T.V.T. and P.V.V. in Vietnam and with B.B., S.K., S.D., A.A., A.K., O.S., C.D. and S.B. in Nepal to coordinate the collection of clinical samples and phenotype data. K.L.A. and C.P.S. coordinated and collected the Vietnamese control cohorts. T.D., D.N.H. and T.A. contributed data from Vietnamese replication cohorts with other diseases. Z.L., K.S.S. and J.N.F. performed genotyping and DNA quality checks on all samples. C.C.K., Y.Y.T., P.I.W.d.B., B.H., Y.O., M.L.H. and S.R. analyzed the data and performed imputation. All authors critically reviewed manuscript revisions and contributed intellectual input to the final submission.

Corresponding authors

Correspondence to Sarah J Dunstan or Chiea Chuen Khor.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Quantile-quantile plot of the association P values obtained in the discovery sample collection.

The two clear outlying SNPs indicated for follow-up assessment are rs6841458 and rs7765379.

Supplementary Figure 2 Principal-component analysis of the discovery sample collection comprising 432 patients with enteric fever and 2,011 controls from Vietnam.

Shown here are plots between the first and second principal components (top panel) and between the first and third principal components (bottom panel). Patients with enteric fever are labeled as cases in red. Controls are labeled in yellow.

Supplementary Figure 3 Principal-component analysis of the Vietnamese enteric fever cases and controls in the context of Asian populations, some of which are from the Asian 1000 Genomes Project.

CDX refers to Chinese Dai individuals from Xishuangbanna, China. CHB refers to Chinese Han in Beijing. CHD refers to Chinese in metropolitan Denver city. CHS refers to Southern Han Chinese. JPT refers to Japanese individuals. KHV refers to Vietnamese Kinh from Ho Chi Minh City. SIMES refers to Singaporean Malays, and SINDI refers to South Indians in Singapore. The upper panel shows all populations so analyzed, whereas the lower panel shows the ancestral matching of the enteric fever cases and controls with more clarity.

Supplementary Figure 4 Manhattan plot of the association P values obtained in the discovery sample collection.

The horizontal red line denotes P = 5 × 10–8, the threshold for genome-wide significance, and the horizontal dotted blue line denotes P = 1 × 10–6. SNPs surpassing genome-wide significance in the discovery collection are labeled.

Supplementary Figure 5 Manhattan plot of the association P values obtained in the discovery sample collection after genome-wide imputation using the 1000 Genomes Project Asian reference panel.

Supplementary Figure 6 Genotyping clouds for SNP rs7765379 across different batches.

Top, Illumina Human Exome BeadChip; bottom, Illumina 660W BeadChip. The genotypes for wild type, heterozygous carrier and homozygous minor allele are clearly distinguished.

Supplementary Figure 7 Genotyping clouds for SNP rs6841458 across different batches.

Top, Salmonella cases, Illumina OmniExpress. Bottom, controls, Illumina 660W BeadChip. The genotypes for wild type, heterozygous carrier and homozygous minor allele are clearly distinguished.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7, Supplementary Tables 1–5 and 7, and Supplementary Note. (PDF 1050 kb)

Supplementary Table 6

List of all 5,422 binary markers within the broad HLA region and the accompanying association results. (XLSX 636 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dunstan, S., Hue, N., Han, B. et al. Variation at HLA-DRB1 is associated with resistance to enteric fever. Nat Genet 46, 1333–1336 (2014). https://doi.org/10.1038/ng.3143

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.3143

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing