Genetic determinants of the severity and duration of the acute sickness response

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Embargoed until 2012-07-04
Copyright: Piraino, Barbara Frances
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Abstract
Acute infective illnesses are accompanied by a set of stereotyped manifestations collectively known as the acute sickness response. These manifestations are mediated by immune and central nervous system events. The first aim of this research was to systematically characterise the acute sickness response in humans, in the setting of natural infection. Principal components analysis of self report data from the Dubbo Infection Outcomes Study (DIOS) – a prospective cohort of individuals followed from the onset of acute Epstein Barr virus, Ross River virus or Q fever infections, determined an overall illness severity phenotype and four endo-phenotypes including fatigue, pain, mood disturbance, and neurocognitive impairment. The acute sickness response varied widely between individuals in severity and duration as well as in the contribution to the illness complex from individual endo-phenotypes. In DIOS, the severity of acute illness predicted duration of illness. The variations of the acute sickness response were verified in a second prospective study of EBV infection - the National Institutes of Health (NIH)-EBV cohort. The influence of genetic polymorphisms on the severity and duration of the acute sickness response was sought using two approaches. Firstly, a candidate gene association study examining functional polymorphisms in immune response genes showed that alleles conferring a heightened pro-inflammatory response were associated with greater illness severity. Another study of functional polymorphisms in neurobehavioural genes showed that individuals with genetically-determined decreased activation of NPY and monoamines were at increased risk of a more severe acute sickness response. Robust associations were shown when high-risk alleles of immunological and neurobehavioral genes were combined suggesting synergy between these genetic factors, thereby depicting plausible host response pathways underpinning the pathophysiology of the acute sickness response. Secondly, a genome wide association study using single nucleotide (SNP)-microarray and pooling (MaP) techniques identified several additional candidates with plausibly relevant roles in immunological events. Only the IFN-γ phenotypic association found in the DIOS cohort was replicated in the NIH-EBV cohort, potentially reflecting limitations in the dataset and sample size available from the latter cohort. The data presented in this thesis provide novel insights into the characteristics of the acute sickness response and its biological basis.
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Author(s)
Piraino, Barbara Frances
Supervisor(s)
Lloyd, Andrew R
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Publication Year
2010
Resource Type
Thesis
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PhD Doctorate
UNSW Faculty
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