Although the clinical efficacy of statins has been well established, there is a wide inter-individual variation in the lipid responses to statins. Pharmacogenetic studies have identified some genetic differences that contribute to the variation, but overall the results have been disappointing. The studies described in this thesis were performed to examine whether certain genetic variants predicted the lipid responses to rosuvastatin in Chinese patients. Over 400 Chinese patients with increased risk of cardiovascular disease (CVD) who were treated with rosuvastatin 10 mg daily for at least 4 weeks (more than 97% of patients had at least 6 weeks treatment) were studied, including 166 having familial hypercholesterolaemia (FH) and 36 having rheumatoid arthritis (RA). They were genotyped for 135 polymorphisms in 62 candidate genes/loci potentially related to pharmacokinetics or pharmacodynamics of statins and lipid metabolism. Associations between genetic polymorphisms and the lipid responses to rosuvastatin were analyzed in 386 patients with good compliance. The associations between genetic polymorphisms and some risk factors for CVD including baseline lipid levels, high-sensitivity C-reactive protein (hsCRP), uric acid and bilirubin levels were also analyzed. / Some novel genetic determinants of the LDL-C response to rosuvastatin treatment have been identified in this study. The responses in HDL-C and triglycerides were related more closely to the baseline levels of these lipids than to any of the polymorphisms examined. Genetic associations with baseline lipid parameters, hsCRP, uric acid and bilirubin were identified and generally correspond with some of the previous reports of studies in Chinese and other ethnic groups. / The key findings of the study are as follows: 1. The polymorphisms most highly associated with the low-density lipoprotein cholesterol (LDL-C) response were 421C>A in the ATP-binding cassette G2 (ABCG2) gene (P=9.2x10 -7), followed by 18281G>A (V257M) in the flavin-containing monooxygenase 3 (FMO3) gene (P=0.0002), 1421C>G in the lipoprotein lipase (LPL) gene (P=0.002), and rs4420638 in the apolipoprotein E/C-I/C-IV/C-II (APOE/C1/C4/C2) gene cluster (P=0.004). These genetic polymorphisms and having FH totally explained 13.6% of the variance in percentage change in LDL-C in response to rosuvastatin. The greater percentage reduction in LDL-C in patients with the ABCG2 421AA genotype compared to those with the ABCG2 421CC genotype was equivalent to at least doubling the dose of rosuvastatin. 2. Three SNPs (glucokinase regulator [ GCKR] rs1260326, apolipoprotein AS [APOA5] -1131T>C and the solute carrier organic anion transporter 1B1 [SLCO1B1] 521T>C) tended to be associated with percentage changes in high-density lipoprotein cholesterol (HDL-C) (P<0.05), but none of these reached the overall significance level. In multivariate stepwise regression analysis, baseline HDL-C (P=1.6x10 -6), having diabetes (P=0.0004) or RA (P=0.002) and the SLCO1B1 521T>C polymorphism (P=0.03) were determinants of HDL-C responses, contributing 9.9% of the variance in percentage change in HDL-C, but the genetic factors only contributed to 0.8% of the variance. 3. The triglyceride response to rosuvastatin was highly variable and was strongly related to baseline levels. The diacylglycerol acyltransferase-2 (DGAT2) rs10899113 C>T polymorphism tended to be associated with reduced triglyceride response in a gene-dose dependent manner. However, in multivariate stepwise regression analysis, baseline triglyceride level was the only factor that strongly related to the triglyceride response, explaining 14.4% of the variance. 4. This study has also analyzed relationships between on-treatment plasma hsCRP concentrations and cardiovascular risk factors and 14 single nucleotide polymorphisms in CRP and other candidate genes, which showed that central obesity, low HDL-C and CRP polymorphisms are major determinants of higher hsCRP levels in Chinese patients on treatment with rosuvastatin. 5. The association between genetic polymorphisms and lipid traits were analyzed in FH and non-FH patients separately due to their different lipid profiles. The analysis has shown that there were different genetic predictors of lipid levels in patients with and without FH and that more genetic factors appeared to affect the baseline lipid levels in patients with FH compared to non-FH patients, suggesting complex interactions between genetic and environmental factors and plasma cholesterol levels in patients with and without FH. 6. The SLC2A9 (solute carrier family 2, member 9) rs1014290 T>C was significantly associated with plasma uric acid levels in a gene-dose dependent manner (P=1.0x10-5) and the relationship was more pronounced in women or in patients without hypertension than in men or patients with hypertension. The ABCG2 421 C>A did not show a significant effect on uric acid levels. 7. The UGT1A1 (uridine diphosphate glucuronosyltransferases family, polypeptide A1) variants *28 (P=1.5x10 -9) and *6 (P=2.2x10-7) were independently associated with increased baseline bilirubin levels. Polymorphisms in SLCO1B1 did not appear to affect bilirubin levels in this study. / Hu, Miao. / Adviser: Brian Tomlinson. / Source: Dissertation Abstracts International, Volume: 72-04, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 230-264). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Xiao, Kang. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 83-103). / Abstracts in English and Chinese. / Abstract --- p.I / 摘要 --- p.VI / Chapter Chapter 1 --- Background --- p.1 / Chapter 1.1 --- Introduction --- p.1 / Chapter 1.2 --- Albuminuria --- p.3 / Chapter 1.2.1 --- Definition --- p.3 / Chapter 1.2.2 --- Albuminuria in adolescents/children --- p.6 / Chapter 1.2.3 --- Prevalence of albuminuria in adults and adolescents --- p.8 / Chapter 1.2.4 --- Pathogenesis of albuminuria --- p.10 / Chapter 1.3 --- CVD and risk factors --- p.12 / Chapter 1.4 --- The associations between microalbuminuria and CVD risk factors --- p.17 / Chapter 1.5 --- Heavy metals --- p.18 / Chapter 1.5.1 --- Definition of heavy metals --- p.18 / Chapter 1.5.2 --- Adverse effects of heavy metals --- p.19 / Chapter 1.5.3 --- Heavy metals exposure In Hong Kong population: the local scene --- p.28 / Chapter 1.6 --- MicroRNAs --- p.29 / Chapter 1.6.1 --- The discovery of microRNAs --- p.29 / Chapter 1.6.2 --- The biogenesis of microRNAs --- p.30 / Chapter 1.6.3 --- The function of microRNAs --- p.31 / Chapter 1.7 --- Hypothesis --- p.40 / Chapter Chapter 2 --- Methodology --- p.41 / Chapter 2.1 --- Population --- p.41 / Chapter 2.2 --- Laboratory assays --- p.42 / Chapter 2.3 --- Statistical analysis --- p.44 / Chapter Chapter 3 --- Results --- p.46 / Chapter 3.1 --- Demographic and baseline clinical data --- p.46 / Chapter 3.2 --- Microalbuminuria and cardiovascular risk factors --- p.48 / Chapter 3.3 --- Microalbuminuria and heavy metals --- p.51 / Chapter 3.4 --- Microalbuminuria and miRNAs --- p.54 / Chapter 3.5 --- "Microalbuminuria, miRNAs, heavy metals and cardiovascular risk factors" --- p.57 / Chapter 3.6 --- miRNAs and heavy metals --- p.60 / Chapter Chapter 4 --- Discussion --- p.62 / Chapter 4.1 --- Heavy metals and microalbuminuria --- p.62 / Chapter 4.2 --- Heavy metals and CVD risk factors --- p.68 / Chapter 4.3 --- Microalbuminuria and CVD risk factors --- p.75 / Chapter 4.4 --- miRNAs and Heavy metals --- p.76 / Chapter 4.5 --- miRNAs and microalbuminuria --- p.77 / Chapter 4.6 --- Conclusion --- p.79 / Acknowledgement --- p.82 / References --- p.83

Abstract not available

Abstract not available

[Truncated abstract] This thesis investigates novel methods for the genetic association analysis of haplotype data in samples of unrelated individuals, and applies these methods to the analysis of coronary heart disease and related phenotypes. Determining the inheritance pattern of genetic variants in studies of unrelated individuals can be problematic because family members of the studied individuals are often not available. For the analysis of individual genetic loci, no problem arises because the unit of interest is the observed genotype. When the unit of interest is the linear combination of alleles along one chromosome, inherited together in a haplotype, it is not always possible to determine with certainty the inheritance pattern, and therefore statistical methods to infer these patterns must be adopted. Due to genotypic heterozygosity, mutliple possible haplotype configurations can often resolve an individual's genotype measures at multiple loci. When haplotypes are not known, but are inferred statistically, an element of uncertainty is thus inherent which, if not dealt with appropriately, can result in unreliable estimates of effect sizes in an association setting. The core aim of the research described in this thesis was to develop and implement a general method for haplotype-based association analysis using multiple imputation to appropriately deal with uncertainty haplotype assignment. Regression-based approaches to association analysis provide flexible methods to investigate the influence of a covariate on a response variable, adjusting for the effects of other variables including interaction terms. ... These methods are then applied to models accommodating binary, quantitative, longitudinal and survival data. The performance of the multiple imputation method implemented was assessed using simulated data under a range of haplotypic effect sizes and genetic inheritance patterns. The multiple imputation approach performed better, on average, than ignoring haplotypic uncertainty, and provided estimates that in most cases were similar to those observed when haplotypes were known. The haplotype association methods developed in this thesis were used to investigate the genetic epidemiology of cardiovascular disease, utilising data for the cholesteryl ester transfer protein gene (CETP), the hepatic lipase (LIPC) gene and the 15- lipoxygenase (ALOX15) gene on a total of 6,487 individuals from three Western Australian studies. Results of these analyses suggested single nucleotide polymorphisms (SNPs) and haplotypes in the CETP gene were associated with increased plasma high-density lipoprotein cholesterol (HDL-C). SNPs in the LIPC gene were also associated with increased HDL-C and haplotypes in the ALOX15 gene were associated with risk of carotid plaque among individuals with premature CHD. The research presented in this thesis is both novel and important as it provides methods for the analysis of haplotypic associations with a range of response types, while incorporating information about haplotype uncertainty inherent in populationbased studies. These methods are shown to perform well for a range of simulated and real data situations, and have been written into a statistical analysis package that has been freely released to the research community.

University of Macau / Institute of Chinese Medical Sciences

published_or_final_version / Community Medicine / Master / Master of Philosophy

Acute Coronary Syndrome (ACS) is common and associated with high mortality. Effective treatments are available but require prompt administration. Studies have consistently demonstrated that delays to treatment are common, with patient decision time accounting for most delay. Interventions aimed at reducing delay have had little success. Evidence suggests that psychological factors, in particular illness representations (Leventhal’s Commonsense Model of Self-Regulation (CS-SRM)) might be important in relation to patient decision time. This thesis describes a two-stage investigation, undertaken within NHS 24, exploring the content and timing of people’s initial presentations with possible symptoms of ACS. The first stage comprised a CS-SRM-guided content analysis of peoples’ initial symptom presentations. The second stage utilised the Illness Perception Questionnaire-revised (IPQ-R) to explore how illness representations relate to patient decision time. Results show that the components of illness representations accounted for 95% of participants’ initial presentations. The components most related to behaviour and outcome were volunteered least (cause, consequences, cure/control and coherence). Decision time for most participants (89%) was out-with the ideal and appraisal time accounted for most of the delay. Appraisal delay was shorter for those with fewer symptoms and high emotion. Illness delay was longer where the person making the call reported high treatment control. Interventions may need to raise awareness of the range of possible presentations and of the consequences associated with delay. Interventions should also provide guidance as to an appropriate time-limit for self-care. Individuals may benefit from being informed about how to respond to strong emotional responses. Interventions aimed at bystanders may need to differ from those for patients. People at high risk of ACS should be informed about how and when to access healthcare out-of-hours.

published_or_final_version / Nursing Studies / Master / Master of Nursing in Advanced Practice

[Formulae and special characters can only be approximated here. Please see the pdf version of the Abtract for an accurate reproduction.] Type 2 diabetes at least doubles the risk of cardiovascular disease. This can partly be explained by the increased prevalence of risk factors such as hypertension, dyslipidaemia and obesity. However, the underlying abnormality of insulin resistance and the presence of more recently identified risk factors including endothelial dysfunction, increased inflammation, and increased oxidative stress might also contribute towards the heightened cardiovascular risk. Fish oil, which contains eicosapentaenoic acid (EPA, 20:5 n-3), has wide-ranging beneficial effects on these and other abnormalities, and has reduced cardiovascular mortality in secondary prevention studies. Animal and human studies have recently established that in addition to EPA, docosahexaenoic acid (DHA, 22:6 n-3) also has beneficial effects, and furthermore, may have less detrimental effects than EPA on glycaemic control which has worsened in some fish and fish oil studies involving Type 2 diabetic subjects. Study 1 : This intervention study aimed to determine the independent effects of EPA and DHA on cardiovascular risk factors and glycaemic control in individuals with Type 2 diabetes receiving treatment for hypertension. In a double-blind placebo-controlled trial of parallel design, 59 subjects in good to moderate glycaemic control (HbA1c < 9%) were recruited from media advertising and randomised to 4 g/day of EPA, DHA or olive oil (placebo) for 6 weeks. Thirty-nine men and 12 post-menopausal women aged 61.2±1.2 yrs completed the study. Relative to placebo, and with Bonferroni adjustments for multiple comparisons, serum triglycerides fell by 19% (p=0.022) and 15% (p=0.022) in the EPA and DHA groups respectively. There were no changes in serum total cholesterol, or LDL- and HDL-cholesterol, although HDL2-cholesterol increased 16% with EPA (p=0.026) and 12% with DHA (p=0.05). HDL3-cholesterol fell by 11% (p=0.026) with EPA supplementation and LDL particle size increased by 0.26±0.10 nm (p=0.02) with DHA. Urinary F2-isoprostanes, an in-vivo marker of oxidative stress was reduced by 19% following EPA (p=0.034) and by 20% following DHA. DHA but not EPA supplementation reduced collagen-stimulated platelet aggregation (16.9%, p=0.05) and thromboxane release (18.8%, p=0.03), but there were no significant changes in PAF-stimulated platelet aggregation. Fasting glucose rose by 1.40±0.29 mmol/l (p=0.002) following EPA and 0.98±0.29 mmol/l (p=0.002) following DHA. Neither EPA nor DHA had any significant effect on HbA1c, fasting serum insulin or C-peptide, insulin sensitivity, stimulated insulin secretion, 24-hr ambulatory blood pressure and heart rate, markers of inflammation, and fibrinolytic or vascular function. Study 2 : This study aimed to examine the influence and causes of increased inflammation on vascular function in subjects recruited for Study 1. Compared with healthy controls (n=17), the diabetic subjects (n=29) had impaired flow-mediated dilatation (FMD) (3.9±3.0% vs 5.5±2.4%, p=0.07) and glyceryl-trinitrate mediated dilatation (GTNMD) (11.4±4.8% vs 15.4±7.1%, p=0.04) of the brachial artery. They also had higher levels of the inflammatory markers C-reactive protein (2.7±2.6 mg/l vs 1.4±1.1 mg/l, p=0.03), fibrinogen (3.4±0.7 g/l vs 2.7±0.3 g/l, p<0.001) and tumor necrosis factor-alpha (20.9±13.4 pg/l vs 2.5±1.7 pg/l, p<0.001). In diabetic subjects, after adjustment for age and gender, leukocyte count was an independent predictor of FMD (p=0.02), accounting for 17% of total variance. Similarly, leukocyte count accounted for 23% (p<0.001) and IL-6 for 12% (p=0.03) of variance in GTNMD. Von Willebrand factor, a marker of endothelial cell activation was correlated with leukocyte count (r=0.38, p=0.04), FMD (r=-0.35, p=0.06) and GTNMD (r=-0.47, p=0.009), whilst P-selectin, a marker of platelet activation was correlated with fibrinogen (r=0.58, p=0.001). Conclusion : EPA and DHA have similar beneficial effects on triglycerides, HDL2 cholesterol and oxidative stress in individuals with Type 2 diabetes and hypertension. However, DHA also increases LDL particle size and reduces collagen-stimulated platelet aggregation and thromboxane release, thus offering more potential than EPA as an anti-thrombotic agent. The beneficial effects of both oils were potentially offset by deterioration in glycaemic control. Neither oil affected blood pressure or vascular function. Longer-term studies with major morbidity and mortality as the primary outcome measures are required to assess the overall benefits and risks of EPA and DHA. The cross-sectional observations from Study 2 are consistent with the hypothesis that impaired vascular function in individuals with Type 2 diabetes and hypertension is at least in part secondary to increased inflammation, with associated endothelial and platelet activation.