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Type: Thesis
Title: Endothelial function & genetic polymorphisms in cerebral small vessel disease: a study investigating the relationship between endothelial function, genetic polymorphisms and cerebral small vessel disease.
Author: Lam, Ada Karman
Issue Date: 2010
School/Discipline: School of Medicine
Abstract: Background: The pathogenesis of cerebral small vessel disease (SVD), encompassing lacunar infarction (LI) and leukoaraiosis (LA), is heterogeneous, with impaired endothelial function (EF) and altered fibrinolysis proposed as important contributors. Genetic factors are involved and may exert their influence via the above mechanisms. The aim of this study was to explore the relationship between EF and SVD, and to examine the role of candidate polymorphisms in both EF and SVD. Methods: The study cohort consisted of patients who had undergone a brain magnetic resonance image (MRI) scan for non-vascular indications. Vascular risk factors were collected by interviewing participants. SVD was classified using a modified Fazekas rating scale, where SVD burden was divided into three categories: absent/mild, moderate and severe. LI was graded separately. EF was assessed using applanation tonometry (ApT) and the radial pulsewave. A global EF score that accounts for both endothelium-dependant and –independent vasodilation was used as the index for comparison. A higher global EF score indicated better EF. Participants were genotyped using the sequence-specific polymerase chain reaction (PCR-SS) for eight candidate polymorphisms chosen based on biological plausibility and/or previous study evidence: interleukin-6 (IL-6) -174 G/C, NADPH oxidase p22 phox 242 C/T, tissue plasminogen activator (tPA) 20324 C/T, tPA -4360 G/C, tPA -7351 C/T, endothelial nitric oxide synthase (eNOS) -786 T/C, endothelin-1 (ET-1) 138 D/I and paraoxonase-1 (PON1) -107 C/T. Statistical analyses were performed using Intercooled Stata 9.2, GraphPad Prism and the SNPstats. Regression models were adjusted for the appropriate variables. Results: A total of 132 participants were assessed. All participants were genotyped and 84 of these 132 participants also had their EF assessed using ApT, but only 72 participants were successful. Participants were graded separately for LI and LA. LA controls (n=119) were defined as participants with absent/mild LA, and LA cases (n=13) were participants with moderate or severe LA. LI controls (n=126) were participants without a radiologically defined LI and LI cases (n=6) were participants with radiologically defined LI. The results of the study can be summarised as follows: 1. there was no significant difference between the EF of cases and controls. Subgroup analyses showed that the risk of LA decreased as the global EF values increased after adjusting for confounding influences, but the relationship was not significant (p=0.23); 2. there were no significant differences in EF between the genotypes of the eight candidate polymorphisms, except for the tPA 20324 C/T, where the TT genotype was associated with higher EF compared to the CC/CT genotypes (p=0.02); 3. the tPA 20324 TT genotype was significantly associated with an increased risk of LI compared to the CC/CT genotypes (p=0.03), although the association is under powered. No other significant associations were found. Although the intent was to achieve a pre-determined sample size, the methodology, and in particular the exclusion criteria, restricted recruitment and consequently the study was under powered to achieve its goals. The study could therefore be considered a pilot study and any conclusions forthwith require validation in a larger sample. Conclusion: The tPA 20324 TT genotype was significantly associated with LI, while also being significantly associated with better EF. This result may be a Type I error reflective of the small sample size. However, the result does support the hypothesis that impaired fibrinolysis has an important pathogenic role in LI. This study does not support impaired EF as a significant pathogenic contributor to SVD.
Advisor: Jannes, Jim
Hamilton-Bruce, Monica Anne
Koblar, Simon Andrea
Dissertation Note: Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2010
Keywords: endothelial function; genetic polymorphisms; cerebral small vessel disease; leukoaraiosis; lacunar infarction
Provenance: Copyright material removed from digital thesis. See print copy in University of Adelaide Library for full text.
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