Drummond, Russell S.
The effect of single nucleotide polymorphisms of oxidative stress genes and low grade inflammation upon pulse wave contour analysis, a useful non invasive, intermediate vascular phenotype.
MD thesis, University of Glasgow.
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Cardiovascular disease remains a major cause of mortality and morbidity and is underpinned by Oxidative stress, within which, inactivation of nitric oxide (NO) by superoxide (SO) and other reactive oxygen species is characteristic. Two major enzyme systems are implicated within oxidative stress; NAD(P)H oxidase and endothelial nitric oxide synthase (eNOS). eNOS generates NO while at the same time, and within the same cells, NAD(P)H plays a powerful role in the generation of SO. Evidence is accumulating that polymorphisms of the genes encoding these enzyme systems may play an important role in the pathophysiology of CAD. Additionally there has been much recent interest in both biochemical markers of oxidative stress and low grade chronic inflammation as well as a non invasive vascular phenotype, pulse wave analysis. This thesis reports a series of studies (utilising the techniques described in chapter 2) which aimed to ascertain:-
The reproducibility of pulse contour analysis as a non invasive intermediate cardiovascular phenotype (Chapter 3).
Whether common single nucleotide polymorphisms of the p22phox gene CYBA and
the endothelial nitric oxide synthase gene, NOS3, have an effect upon arterial compliance in patients with coronary artery disease (Chapters 4,5 and 6).
In healthy volunteers, free of cardiovascular disease whether a relationship existed between markers of low grade inflammation and arterial stiffness (Chapter 7).
Chapter 3: The reproducibility of diastolic pulse wave contour analysis and its relation to systolic pulse contour analysis.
This clinical study demonstrated that both large (C1) and small artery (C2) compliance values were reproducible and that there was a significant correlation between both Augmentation Index (AIx) and C1and AIx and C2 in healthy volunteers and though there was no association
between AIx and C1 in patients with coronary artery disease AIx did correlate with C2 in this population.
Chapter 4: The effect of the G894T SNP of the NOS3 gene upon arterial stiffness in patients with coronary artery disease.
There was no association observed between this polymorphism and blood pressure or large artery compliance however ANOVA revealed a statistically significant association for TT homozygosity and small artery compliance. The highest small artery compliance was seen in the patients homozygous for the G allele, an intermediate value observed in heterozygotes and the lowest value demonstrated in patients homozygous for the T allele. Multiple regression analysis, examining the possible contribution of confounders showed that only small artery compliance was significant when NOS3 G894T genotype was assigned as the dependent variable.
Chapter 5: The C242T single nucleotide polymorphism of the CYBA gene and blood pressure and arterial compliance in patients with coronary artery disease.
We sought to examine the influence of the C242T SNP of CYBA upon vascular compliance and blood pressure using the dominant allele model. The presence of the 242T allele was associated with significantly higher systolic blood pressure. Patients homozygous for the C allele had lower systolic blood pressure than heterozygotes and patients homozygous for the T allele. There was no statistically significant effect upon diastolic blood pressure but there was however a significant association observed between the 242T allele and pulse pressure.
Chapter 6: Combined analysis of NOS3 G894T and CYBA C242T genotypes upon arterial stiffness.
In order to contrast the arterial stiffness between the favourable versus the non-favourable genotypes patients homozygous for the NOS3 G allele and homozygous for the CYBA C allele were compared with those homozygous for the NOS3T allele and possessing the CYBA 242T allele. The former displayed higher large and small artery compliance than the latter group. Multiple regression analysis, examining the possible contribution of confounders showed that only the large and small artery compliance values contributed significantly when genotype was assigned as the dependent variable.
Chapter 7 Chronic low grade inflammation and insulin resistance and arterial compliance in healthy volunteers.
Within healthy volunteers multiple regression analysis showed that small artery compliance was significantly associated with IL 6, CRP and ICAM. Augmentation index showed only an association with ICAM1. There was no significant correlation between Adiponectin levels and either of the arterial stiffness parameters studied.
Diastolic pulse wave contour analysis is a reproducible assessment of arterial stiffness with the potential to represent a high fidelity non invasive vascular phenotype.
Small artery compliance is correlated with Augmentation Index and although the measurements are not analogous they both represent useful means of acquiring quantitative data concerning arterial stiffness.
The 242T allele of the p22phox gene, CYBA, is associated with decreased large but not small artery compliance and increased systolic and pulse pressure.
Homozygosity for a common NOS3 polymorphism (894 GT) was associated with decreased small artery compliance but not with large artery compliance or blood pressure.
The markers of chronic inflammation Interleukin 6, ICAM and hsCRP but not Adiponectin, a marker of Insulin resistance, predict small artery compliance in healthy individuals apparently free of vascular disease.
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