Brull, David Joseph; (2002) Inflammation and atherosclerosis: The role of genetic polymorphisms in cardiovascular pathophysiology. Doctoral thesis (M.D), UCL (University College London).

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Abstract

Introduction: Elevated markers of systemic inflammation are associated with cardiovascular risk - an association that may be causally mediated by intereukin-6 (IL6), β-fibrinogen and C-reactive protein (CRP). This hypothesis may be explored using polymorphic variants in these genes as tools. The aim of this thesis was to address whether such polymorphisms were functional in vivo. Methods: Military exercise (ME) and coronary artery bypass graft surgery (CABG) were utilised as models of inflammatory response to investigate whether the IL6 -572G>C and -174G>C; β-fibrinogen -854G>A and -455G>A: and CRP -748G>A, +1059G>C and + 1444>T polymorphisms were functional. DNA extracted from peripheral blood was amplified by polymerase chain reaction and genotypes resolved by electrophoresis following restriction enzyme digestion. Results: One hundred and ninety three subjects undergoing elective CABG were studied. Serum IL6, CRP and fibrinogen were measured preoperatively and during the first five post-operative days. Analyses suggested a significant effect of both IL6 polymorphisms on peak post-CABG IL6 (highest for genotypes -174CC and -572GC/CC). Fibrinogen - 455AA genotype was associated with an earlier rise in fibrinogen but no effect on peak response, whilst peak CRP was significantly higher for subjects of CRP genotype +1444TT. In the second study IL6, CRP and fibrinogen were measured before and after a 48-hour military exercise in 250 male army recruits. Whilst there was no association between IL6 genotype and baseline IL6, post-ME IL6 was significantly lower in -572C-allele carriers. Additionally, subjects of genotype -572GC and -174CC had the lowest post-ME fibrinogen. Post-ME fibrinogen was higher in carriers of the β-fibrinogen -455A- allele. CRP levels were significantly higher both before and after ME in recruits of genotype +1444TT. Conclusions: These data support the in vivo functionality of the IL6 -174G>C and -572G>C; β-fibrinogen -455G>A and CRP +1444C>T polymorphisms and suggest that they might be applied in future candidate gene-association studies investigating cardiovascular disease.

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