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

Abstract

The genomic region surrounding the TNF locus on human chromosome 6 has previously been associated with typhoid fever in Vietnam. 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.

Genetic susceptibility to invasive Salmonella disease

“…A community-based, case-control study in Indonesian patients with enteric fever demonstrated no association at three TNF and TNF receptor superfamily, member 1A (TNFRSF1A) genetic variants 38 . By contrast, a case-control study of enteric fever in a Vietnamese population identified a protective effect of an MHC class III haplotype, which included the TNF gene, against enteric fever 59 . Patients with enteric fever and the protective haplotype were shown to produce statistically significantly less TNF ex vivo on whole blood stimulation with LPS on day four of disease 59 .…”

“…By contrast, a case-control study of enteric fever in a Vietnamese population identified a protective effect of an MHC class III haplotype, which included the TNF gene, against enteric fever 59 . Patients with enteric fever and the protective haplotype were shown to produce statistically significantly less TNF ex vivo on whole blood stimulation with LPS on day four of disease 59 . However, this finding should be interpreted with caution, as this effect was not seen in a better-powered GWAS of enteric fever in the same population 6 .…”

Salmonella infections in immunocompromised adults

“…Resistance to typhoid fever is, however, associated with a protective haplotype in the TNF region on chromosome 6, within the MHC class II locus. 9 HIV does not seem to be associated with an increased susceptibility to, or worse outcome of typhoid fever. Gotuzzo et al described eight patients with HIV and typhoid in Peru, four with unusually severe diarrhoea or colitis, and two with relapse after treatment.…”

Epidemiology, Clinical Presentation, Laboratory Diagnosis, Antimicrobial Resistance, and Antimicrobial Management of Invasive Salmonella Infections

“…Of interest, HLA-DR haplotypes were associated with protection from severe enteric fever among Indonesian patients, although this could not be linked with TNF-␣ production capacity (31). Further analysis of the Vietnamese population again suggested that a haplotype in the TNF region gives protection against enteric fever, but the causative disease locus remains to be determined (32). In a recent genome-wide association study of patients in Vietnam and Nepal with blood culture-confirmed enteric fever, a strong association was found for HLA-DRB1 as a major contributor to resistance against enteric fever, presumably through antigen presentation (33).…”