Human Genetics

, Volume 122, Issue 1, pp 51–61 | Cite as

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

  • Sarah J. Dunstan
  • Nguyen Thi Hue
  • Kirk Rockett
  • Julian Forton
  • Andrew P. Morris
  • Mahamadou Diakite
  • Mai Ngoc Lanh
  • Le Thi Phuong
  • Deborah House
  • Christopher M. Parry
  • Ha Vinh
  • Nguyen T. Hieu
  • Gordon Dougan
  • Tran Tinh Hien
  • Dominic Kwiatowski
  • Jeremy J. Farrar
Original Investigation

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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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Sarah J. Dunstan
    • 1
    • 2
  • Nguyen Thi Hue
    • 1
    • 3
  • Kirk Rockett
    • 4
  • Julian Forton
    • 4
  • Andrew P. Morris
    • 4
  • Mahamadou Diakite
    • 4
  • Mai Ngoc Lanh
    • 5
  • Le Thi Phuong
    • 5
  • Deborah House
    • 6
  • Christopher M. Parry
    • 1
    • 7
  • Ha Vinh
    • 3
  • Nguyen T. Hieu
    • 8
  • Gordon Dougan
    • 6
  • Tran Tinh Hien
    • 3
  • Dominic Kwiatowski
    • 4
  • Jeremy J. Farrar
    • 1
    • 2
  1. 1.Oxford University Clinical Research UnitHospital for Tropical DiseasesHo Chi Minh CityVietnam
  2. 2.Centre for Tropical Medicine, Nuffield Department of Clinical MedicineOxford UniversityOxfordUnited Kingdom
  3. 3.Hospital for Tropical DiseasesHo Chi Minh CityVietnam
  4. 4.Wellcome Trust Centre for Human GeneticsOxford UniversityOxfordUK
  5. 5.Dong Thap Provincial HospitalDong ThapVietnam
  6. 6.Wellcome Trust Sanger Centre HinxtonCambridgeUK
  7. 7.Department of Medical Microbiology and Genitourinary MedicineUniversity of LiverpoolLiverpoolUK
  8. 8.Hung Vuong HospitalHo Chi Minh CityVietnam

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