Original Investigation

Human Genetics

, Volume 122, Issue 1, pp 51-61

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

  • Sarah J. DunstanAffiliated withOxford University Clinical Research Unit, Hospital for Tropical DiseasesCentre for Tropical Medicine, Nuffield Department of Clinical Medicine, Oxford University Email author 
  • , Nguyen Thi HueAffiliated withOxford University Clinical Research Unit, Hospital for Tropical DiseasesHospital for Tropical Diseases
  • , Kirk RockettAffiliated withWellcome Trust Centre for Human Genetics, Oxford University
  • , Julian FortonAffiliated withWellcome Trust Centre for Human Genetics, Oxford University
  • , Andrew P. MorrisAffiliated withWellcome Trust Centre for Human Genetics, Oxford University
  • , Mahamadou DiakiteAffiliated withWellcome Trust Centre for Human Genetics, Oxford University
  • , Mai Ngoc LanhAffiliated withDong Thap Provincial Hospital
  • , Le Thi PhuongAffiliated withDong Thap Provincial Hospital
  • , Deborah HouseAffiliated withWellcome Trust Sanger Centre Hinxton
    • , Christopher M. ParryAffiliated withOxford University Clinical Research Unit, Hospital for Tropical DiseasesDepartment of Medical Microbiology and Genitourinary Medicine, University of Liverpool
    • , Ha VinhAffiliated withHospital for Tropical Diseases
    • , Nguyen T. HieuAffiliated withHung Vuong Hospital
    • , Gordon DouganAffiliated withWellcome Trust Sanger Centre Hinxton
    • , Tran Tinh HienAffiliated withHospital for Tropical Diseases
    • , Dominic KwiatowskiAffiliated withWellcome Trust Centre for Human Genetics, Oxford University
    • , Jeremy J. FarrarAffiliated withOxford University Clinical Research Unit, Hospital for Tropical DiseasesCentre for Tropical Medicine, Nuffield Department of Clinical Medicine, Oxford University

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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.