Thompson, S.R.; (2007) Genetic variation within the IL-18 system and its association with cardiovascular disease and obesity. Doctoral thesis , University of London.

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Abstract

Background and Aims: The interleukin 18 (IL-18) system consists of a pro inflammatory cytokine (IL-18), a naturally occurring inhibitor (IL-18BP), and a dimeric receptor. IL-18 has been implicated in many autoimmune conditions, with elevated plasma levels predicting future risk of heart disease in healthy individuals. IL-18 also appears to have metabolic consequences, with M8 / mice having higher bodyweight, attributable to increased feeding. The central hypothesis of this work was that genetic variation within both IL-18 and IL18BP, that influenced their circulating levels, would be associated with individual risk for both heart disease and obesity. This was tested by measuring IL-18 levels in several study groups and accessing their correlation with numerous single nucleotide polymorphisms (SNPs) (chosen using a tagging SNP (tSNP) methodology) within both genes. Any effects (either single SNP or haplotypic) were then assessed directly using quantitative PCR (QPCR). Results: For both IL18 and ILI8BP, tSNP sets were chosen that captured greater than 90% of the common genetic variation seen in a representative European Caucasian sample. Their association with levels of IL-18 and interleukin 18 binding protein (IL-18BP) were assessed in healthy and diseased individuals genetic variation in IL-18 only was associated with differences in plasma IL-18 (and free IL-18 (fIL-18)) levels in all cohorts. Carriage of the rare allele of /L/S-5848 T>C was associated with, on average across all study groups, 44% higher IL-18 levels than TT homozygotes. There was also a haplotypic effect, with a common haplotype---hGTATA (frequency of 20%)---being associated with 30% lower IL-18 levels. The effect was consistently of greater magnitude in diseased than healthy individuals. Despite IL-18 levels being elevated in those individuals who went on to suffer an myocardial infarction (MI) over 15 yr of follow-up (277.6 pg/ml vs. 239.6 pg/ml, p=0.05), there was no significant difference in genotype, or haplotype, frequencies in those who had heart disease compared to those who did not. No consistent association between BMI/obesity and IL-18 levels was observed, however, in two of the study groups genetic variation in IL18 was associated with significant differences in body mass index (BMI). Overall, hGTATA was associated with a 9% higher BMI, equating to a 7 kg greater body weight for an average male. In in vitro studies of IL-18 expression in healthy, male hGTATA carriers, no significant difference in 1L-18 messenger RNA (mRNA) concentrations were observed when compared to hGCATA controls. Conclusion: The data presented here disagrees with previously published results, showing no role for variation within IL18 in establishing heart disease risk. However there are novel findings that suggest it may play a role in weight control. Given that these effects appear not to be mediated through plasma IL-18 levels, the identification of individuals through genetic testing may be especially relevant.

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