The host genetics of typhoid fever in Vietnam

Nguyen Thi Hue (2007). The host genetics of typhoid fever in Vietnam. PhD thesis The Open University.



Typhoid fever is a systemic infection caused by the bacterium Salmonella enterica serovar Typhi. It remains a major public health problem throughout the developing world with over 22 million people infected each year. The emergence of resistance to chloramphenicol and other antimicrobials has been a major setback and we now face the very real prospect that untreatable typhoid fever will emerge. Understanding host genetics may yield answers that lead to the development of new therapeutics for infectious disease such as typhoid fever. Using a genetic approach we aim to investigate a number of immune response genes that may be important in the defense against typhoid fever. Here we describe studies investigating the genetic variation within some human innate immunity genes which may play an important role in susceptibility to typhoid fever. The TLR4 gene encoding the principal receptor for bacterial endotoxin recognition, an element of innate immunity that contributes to the first line of defense against infectious disease was investigated. We determined the extent of genetic variation within TLR4 in a Vietnamese kinh population and identified a number of novel missense mutations. It appears that this gene may be involved in defense against typhoid fever, as evidenced by weak associations with two SNPs and the presence of low frequency non-synonymous SNPs in only typhoid fever cases which may have the potential to alter protein function. The haplotypic structure of a 150Kb genomic region encompassing TNFA was determined in a Vietnamese population. This allowed the identification of 15 haplotype tagging SNPs which were genotyped in a case/control genetic association study. Seven polymorphisms across three key genes in the TNF region were associated with typhoid fever. A haplotype spanning this region (*12122*1111) was strongly associated with protection from typhoid fever. Polymorphisms in the chemokine and other immune response gene cluster on chromosome 17q11.22-q22 were also investigated. Our results show that the NOS2A gene within this region, which encodes iNOS, plays an important role in typhoid fever as polymorphisms within NOS2A were shown to be associated with protection from typhoid fever. A number of genes or genomic regions encoding components of the innate and acquired immune responses contribute to an individual’s ability to mount an appropriate immune response to S. typhi infection during typhoid fever. Genetic variation in any of these genes may lead to the alteration of the host immune response with deleterious effects. Together with environmental factors and pathogen virulence, host genetic factors contribute to typhoid fever susceptibility, and studies of candidate genes and genomic regions add to our overall understanding of protective disease mechanisms.

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