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A TNF region haplotype offers protection from typhoid fever in Vietnamese patients

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Abstract

The genomic region surrounding the TNF locus on human chromosome 6 has previously been associated with typhoid fever in Vietnam (Dunstan et al. in J Infect Dis 183:261–268, 2001). We used a haplotypic approach to understand this association further. Eighty single nucleotide polymorphisms (SNPs) spanning a 150 kb region were genotyped in 95 Vietnamese individuals (typhoid case/mother/father trios). A subset of data from 33 SNPs with a minor allele frequency of >4.3% was used to construct haplotypes. Fifteen SNPs, which tagged the 42 constructed haplotypes were selected. The haplotype tagging SNPs (T1–T15) were genotyped in 380 confirmed typhoid cases and 380 Vietnamese ethnically matched controls. Allelic frequencies of seven SNPs (T1, T2, T3, T5, T6, T7, T8) were significantly different between typhoid cases and controls. Logistic regression results support the hypothesis that there is just one signal associated with disease at this locus. Haplotype-based analysis of the tag SNPs provided positive evidence of association with typhoid (posterior probability 0.821). The analysis highlighted a low-risk cluster of haplotypes that each carry the minor allele of T1 or T7, but not both, and otherwise carry the combination of alleles *12122*1111 at T1–T11, further supporting the one associated signal hypothesis. Finally, individuals that carry the typhoid fever protective haplotype *12122*1111 also produce a relatively low TNF-α response to LPS.

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References

  • Abecasis GR, Cookson WO (2000) GOLD-graphical overview of linkage disequilibrium. Bioinformatics 16:182–183

    Article  PubMed  CAS  Google Scholar 

  • Ackerman H, Usen S, Mott R, Richardson A, Sisay-Joof F, Katundu P, Taylor T, Ward R, Molyneux M, Pinder M, Kwiatkowski DP (2003a) Haplotypic analysis of the TNF locus by association efficiency and entropy. Genome Biol 4:R24

    Article  PubMed  Google Scholar 

  • Ackerman HC, Ribas G, Jallow M, Mott R, Neville M, Sisay-Joof F, Pinder M, Campbell RD, Kwiatkowski DP (2003b) Complex haplotypic structure of the central MHC region flanking TNF in a West African population. Genes Immun 4:476–486

    Article  PubMed  CAS  Google Scholar 

  • Allcock RJ, Williams JH, Price P (2001) The central MHC gene, BAT1, may encode a protein that down-regulates cytokine production. Genes Cells 6:487–494

    Article  PubMed  CAS  Google Scholar 

  • Allcock RJ, Atrazhev AM, Beck S, de Jong PJ, Elliott JF, Forbes S, Halls K, Horton R, Osoegawa K, Rogers J, Sawcer S, Todd JA, Trowsdale J, Wang Y, Williams S (2002) The MHC haplotype project: a resource for HLA-linked association studies. Tissue Antigens 59:520–521

    Article  PubMed  CAS  Google Scholar 

  • Altshuler D, Brooks LD, Chakravarti A, Collins FS, Daly MJ, Donnelly P (2005) A haplotype map of the human genome. Nature 437:1299–1320

    Article  CAS  Google Scholar 

  • Bhutta ZA, Mansoorali N, Hussain R (1997) Plasma cytokines in paediatric Typhoidal salmonellosis: correlation with clinical course and outcome. J Infect 35:253–256

    Article  PubMed  CAS  Google Scholar 

  • Cabrera M, Shaw MA, Sharples C, Williams H, Castes M, Convit J, Blackwell JM (1995) Polymorphism in tumor necrosis factor genes associated with mucocutaneous leishmaniasis. J Exp Med 182:1259–1264

    Article  PubMed  CAS  Google Scholar 

  • Chinh NT, Parry CM, Ly NT, Ha HD, Thong MX, Diep TS, Wain J, White NJ, Farrar JJ (2000) 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

    Article  PubMed  CAS  Google Scholar 

  • Cordell HJ, Clayton DG (2002) A unified stepwise regression procedure for evaluating the relative effects of polymorphisms within a gene using case/control or family data: application to HLA in type 1 diabetes. Am J Hum Genet 70:124–141

    Article  PubMed  CAS  Google Scholar 

  • Crump JA, Luby SP, Mintz ED (2004) The global burden of typhoid fever. Bull World Health Org 82:346–353

    PubMed  Google Scholar 

  • Daly MJ, Rioux JD, Schaffner SF, Hudson TJ, Lander ES (2001) High-resolution haplotype structure in the human genome. Nat Genet 29:229–232

    Article  PubMed  CAS  Google Scholar 

  • Dharmana E, Joosten I, Tijssen HJ, Gasem MH, Indarwidayati R, Keuter M, Dolmans WM, Van Der Meer JW (2002) HLA-DRB1*12 is associated with protection against complicated typhoid fever, independent of tumour necrosis factor alpha. Eur J Immunogenet 29:297–300

    Article  PubMed  CAS  Google Scholar 

  • Dunstan SJ, Stephens HA, Blackwell JM, Duc CM, Lanh MN, Dudbridge F, Phuong CX, Luxemburger C, Wain J, Ho VA, Hien TT, Farrar J, Dougan G (2001) Genes of the class II and class III major histocompatibility complex are associated with typhoid fever in Vietnam. J Infect Dis 183:261–268

    Article  PubMed  CAS  Google Scholar 

  • Durrant C, Zondervan KT, Cardon LR, Hunt S, Deloukas P, Morris AP (2004) Linkage disequilibrium mapping via cladistic analysis of single-nucleotide polymorphism haplotypes. Am J Hum Genet 75:35–43

    Article  PubMed  CAS  Google Scholar 

  • Forton J, Kwiatkowski D, Rockett K, Luoni G, Kimber M, Hull J (2005) Accuracy of haplotype reconstruction from haplotype-tagging single-nucleotide polymorphisms. Am J Hum Genet 76:438–448

    Article  PubMed  CAS  Google Scholar 

  • Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, Altshuler D (2002) The structure of haplotype blocks in the human genome. Science 296:2225–2229

    Article  PubMed  CAS  Google Scholar 

  • Hoa NT, Diep TS, Wain J, Parry CM, Hien TT, Smith MD, Walsh AL, White NJ (1998) Community-acquired septicaemia in southern Viet Nam: the importance of multidrug-resistant Salmonella typhi. Trans R Soc Trop Med Hyg 92:503–508

    Article  PubMed  CAS  Google Scholar 

  • House D, Chinh NT, Hien TT, Parry CP, Ly NT, Diep TS, Wain J, Dunstan S, White NJ, Dougan G, Farrar JJ (2002) Cytokine release by lipopolysaccharide-stimulated whole blood from patients with typhoid Fever. J Infect Dis 186:240–245

    Article  PubMed  CAS  Google Scholar 

  • Johnson GC, Esposito L, Barratt BJ, Smith AN, Heward J, Di Genova G, Ueda H, Cordell HJ, Eaves IA, Dudbridge F, Twells RC, Payne F, Hughes W, Nutland S, Stevens H, Carr P, Tuomilehto-Wolf E, Tuomilehto J, Gough SC, Clayton DG, Todd JA (2001) Haplotype tagging for the identification of common disease genes. Nat Genet 29:233–237

    Article  PubMed  CAS  Google Scholar 

  • Keuter M, Dharmana E, Gasem MH, van der Ven-Jongekrijg J, Djokomoeljanto R, Dolmans WM, Demacker P, Sauerwein R, Gallati H, van der Meer JW (1994) Patterns of proinflammatory cytokines and inhibitors during typhoid fever. J Infect Dis 169:1306–1311

    PubMed  CAS  Google Scholar 

  • Knight JC, Udalova I, Hill AV, Greenwood BM, Peshu N, Marsh K, Kwiatkowski D (1999) A polymorphism that affects OCT-1 binding to the TNF promoter region is associated with severe malaria. Nat Genet 22:145–150

    Article  PubMed  CAS  Google Scholar 

  • Lin FY, Vo AH, Phan VB, Nguyen TT, Bryla D, Tran CT, Ha BK, Dang DT, Robbins JB (2000) The epidemiology of typhoid fever in the Dong Thap Province, Mekong Delta region of Vietnam. Am J Trop Med Hyg 62:644–648

    PubMed  CAS  Google Scholar 

  • Luxemburger C, Chau MC, Mai NL, Wain J, Tran TH, Simpson JA, Le HK, Nguyen TT, White NJ, Farrar JJ (2001) 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

    Article  PubMed  CAS  Google Scholar 

  • Migita O, Noguchi E, Koga M, Jian Z, Shibasaki M, Migita T, Ito S, Ichikawa K, Matsui A, Arinami T (2005) Haplotype analysis of a 100 kb region spanning TNF-LTA identifies a polymorphism in the LTA promoter region that is associated with atopic asthma susceptibility in Japan. Clin Exp Allergy 35:790–796

    Article  PubMed  CAS  Google Scholar 

  • Moffatt MF, Cookson WO (1997) Tumour necrosis factor haplotypes and asthma. Hum Mol Genet 6:551–554

    Article  PubMed  CAS  Google Scholar 

  • Morris AP (2005) Direct analysis of unphased SNP genotype data in population-based association studies via Bayesian partition modelling of haplotypes. Genet Epidemiol 29:91–107

    Article  PubMed  Google Scholar 

  • Parry CM, Hien TT, Dougan G, White NJ, Farrar JJ (2002) Typhoid fever. N Engl J Med 347:1770–1782

    Article  PubMed  CAS  Google Scholar 

  • Phuong CXT, Kneen R, Nguyen TA, Truong DL, White NJ, Parry CM (1999) 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

    Article  Google Scholar 

  • Stephens M, Smith NJ, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68:978–989

    Article  PubMed  CAS  Google Scholar 

  • The International HapMap Project (2003) Nature 426:789–796

    Article  CAS  Google Scholar 

  • The MHC sequencing Consortium (1999) Complete sequence and gene map of a human major histocompatibility complex. Nature 401:921–923

    Article  Google Scholar 

  • Vinh H, Parry CM, Hanh VT, Chinh MT, House D, Tham CT, Thao NT, Diep TS, Wain J, Day NP, White NJ, Farrar JJ (2004) Double blind comparison of ibuprofen and paracetamol for adjunctive treatment of uncomplicated typhoid fever. Pediatr Infect Dis J 23:226–230

    Article  PubMed  Google Scholar 

  • Walsh EC, Mather KA, Schaffner SF, Farwell L, Daly MJ, Patterson N, Cullen M, Carrington M, Bugawan TL, Erlich H, Campbell J, Barrett J, Miller K, Thomson G, Lander ES, Rioux JD (2003) An integrated haplotype map of the human major histocompatibility complex. Am J Hum Genet 73:580–590

    Article  PubMed  CAS  Google Scholar 

  • Zeggini E, Thomson W, Kwiatkowski D, Richardson A, Ollier W, Donn R (2002) Linkage and association studies of single-nucleotide polymorphism-tagged tumor necrosis factor haplotypes in juvenile oligoarthritis. Arthritis Rheum 46:3304–11

    Article  PubMed  CAS  Google Scholar 

  • Zhang L, Cui X, Schmitt K, Hubert R, Navidi W, Arnheim N (1992) Whole genome amplification from a single cell: implications for genetic analysis. Proc Natl Acad Sci USA 89:5847–5851

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We acknowledge with thanks the directors and the staff of the Hospital for Tropical Disease, Dong Thap Provincial Hospital, Dong Nai Pediatric Hospital and Hung Vuong Hospital, Viet Nam for the clinical and microbiological work associated with this study. We thank the Vietnamese individuals who took part in this study. The Wellcome Trust funded this work.

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Correspondence to Sarah J. Dunstan.

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Dunstan, S.J., Hue, N.T., Rockett, K. et al. A TNF region haplotype offers protection from typhoid fever in Vietnamese patients. Hum Genet 122, 51–61 (2007). https://doi.org/10.1007/s00439-007-0372-9

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  • DOI: https://doi.org/10.1007/s00439-007-0372-9

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