A TNF region haplotype offers protection from typhoid fever in Vietnamese patients.
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-alpha response to LPS.
Dunstan
Sarah J
SJ
Oxford University Clinical Research Unit, Hospital for Tropical Diseases, 190 Ben Ham Tu, Quan 5, District 5, Ho Chi Minh City, Vietnam. sdunstan@oucru.org
Nguyen
Thi Hue
TH
Rockett
Kirk
K
Forton
Julian
J
Morris
Andrew P
AP
Diakite
Mahamadou
M
Mai
Ngoc Lanh
NL
Le
Thi Phuong
TP
House
Deborah
D
Parry
Christopher M
CM
Ha
Vinh
V
Nguyen
T Hieu
TH
Dougan
Gordon
G
Tran
Tinh Hien
TH
Kwiatowski
Dominic
D
Farrar
Jeremy J
JJ
D016022:Case-Control Studies; D002874:Chromosome Mapping; D016000:Cluster Analysis; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism; D014435:Typhoid Fever / Q000235:genetics* / Q000378:metabolism; D014744:Vietnam
D014409:Tumor Necrosis Factor-alpha