George, Sara K.; (2003) The effect of cytokine gene polymorphisms on renal transplantation and atherosclerosis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

BACKGROUND: Genetic variability in cytokine production could influence the outcome of immune and inflammatory responses. Renal transplantation, which is considered to be the most efficient form of renal replacement therapy for patients with end stage renal disease, is adversely affected by acute rejection, chronic allograft dysfunction, and accelerated atherosclerosis. The aim of this thesis was to explore the influence of cytokine gene polymorphism on acute rejection, chronic allograft dysfunction, and atherosclerosis. METHODS: 113 kidney allograft recipients, 66 atherosclerotic renal artery stenosis patients and 100 normal (control) individuals were genotyped for single nucleotide polymorphisms of TNF-alpha, IL-2, IL-6, IL-10, and TGF-beta genes. Microsatellite polymorphisms of IFN-gamma, IL-10G, IL-10R, TNF-a and TNF-d were also investigated. Each cytokine gene polymorphism was studied for its influence on secretory status in vitro. RESULTS: The frequencies of IL-10 (-1082) AA, GA (low producer) genotypes and TNF-a9 microsatellite allele were high, independently, in individuals with more than one episode of acute allograft rejection when compared to rejection free patients after renal transplantation. The frequencies of IL-10 (-1082) AA, GA genotypes were also high in individuals with chronic allograft dysfunction within five years post transplant. Similarly, the frequencies of IL-10 (-1082) AA, GA genotypes were high in renal artery stenosis patients when compared to normal healthy controls. There was increased production of IL-10 mRNA and protein in individuals with the IL-10 (-1082GG) genotype compared to IL-10 (GA and AA) genotypes. Other cytokine gene polymorphism did not show any association with either renal transplant outcome or atherosclerosis. CONCLUSION: These results suggest that IL-10 (-1082) promoter and TNF-a microsatellite polymorphisms independently may predict the development of acute rejection after renal transplantation. The results also suggest that IL-10 may have an important role in regulating inflammatory signals in the pathogenesis of both chronic allograft rejection and atherosclerosis.

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