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Cardiovascular disease (CVD) is highly prevalent in chronic kidney disease (CKD) patients. Whilst this can in part be explained by the high incidence of traditional CVD risk factors such as hypertension and diabetes evident in CKD patients, recent focus has been on non-traditional risk factors and their role in CVD progression. These include endothelial dysfunction, arterial stiffness, inflammation and oxidative stress. The potent vasoconstrictor endothelin-1 (ET-1) has been implicated in the pathogenesis of CKD and the CVD associated with it. Further understanding of the mechanisms by which it contributes to CKD and CVD pathogenesis, specifically its interactions with non-traditional risk factors are still required. Additionally, the potential applications of ET antagonists in renal disease have not been fully explored. This thesis aims to investigate the role of ET-1 in the development of renal disease and the associated inflammation, hypertension and vascular dysfunction through a series of in vitro, in vivo and clinical studies. I have demonstrated using in vitro techniques that murine macrophages (Mϕ) express both endothelin A (ETA) and endothelin B (ETB) receptors but that ET-1 does not elicit either a classical pro-inflammatory or alternative anti-inflammatory phenotype in Mϕ. I was however, able to show that M display chemokinesis towards ET-1 and M ETB receptors provide a novel clearance mechanism for ET-1 through receptor mediated dynamin-dependent endocytosis In an in vivo study I investigated whether ET-1 mediates the progressive renal injury after renal ischaemia reperfusion injury (IRI) that leads to the development of CKD. I demonstrated that endothelin A receptor antagonism provided long term beneficial effects reducing blood pressure and preventing progressive kidney injury, inflammation, and the development of fibrosis resulting from an episode of acute kidney injury (AKI). Similar benefits were observed with calcium channel blockade, suggesting hypertension may mediate some of the long term effects of renal IRI and anti-hypertensive treatments could prevent the development of CKD after AKI. Finally, in a clinical study I showed for the first time that CKD patients lack the diurnal variation in arterial stiffness that is seen in matched subjects without CKD. Alteration in the circadian variation of the ET-1 system may contribute to this. In summary, my studies have furthered our understanding of the role of ET-1 in CKD progression and the cardiovascular risk associated with it. Mϕ were shown to express both ET receptors and a novel mechanism of ET-1 clearance was observed in Mϕ. Using an in vivo model of AKI I was able to identify ETA receptor antagonism as a novel therapeutic agent in preventing the development of CKD caused by AKI where data are limited. Finally, alterations in the circadian rhythm of the cardiovascular system is emerging as an important factor in disease pathogenesis. Here the diurnal variation in arterial stiffness was described for the first time in a group of CKD patients and matched controls.

Regular aerobic exercise may reduce cardiovascular disease (CVD) risk in part by lowering the concentration of inflammatory markers such as C-reactive protein (CRP). While studies in diseased populations have shown significant decreases in CRP concentrations with regular aerobic training, little has been conclusively determined regarding the effects of aerobic training on CRP concentrations in apparently healthy, untrained populations who may not be adequately screened for CVD risk by traditional methods. PURPOSE: To examine the effects of a 17-wk half marathon training program (TP) on CRP concentrations, aerobic fitness, and body composition in apparently healthy, untrained men. METHODS: Twenty men (29.3 ± 1.0 yr, 37.0 ± 1.6 mL•kg-1•min-1 VO2max, 29.1 ± 1.8% body fat) registered as training subjects (TRN) in a 17-wk half marathon TP. An additional 22 men (27.8 ± 1.4 yr, 38.8 ± 1.0 mL•kg-1•min-1 VO2max, 26.8 ± 1.4% BF) served as controls (CON). Fasting blood samples were taken at four time points over the TP and were analyzed for CRP and interleukin-6 (IL-6) concentrations. Aerobic capacity (VO2max) and body fat (BF%) were measured before and after the TP. RESULTS: No significant changes in CRP (P=0.69) or IL-6 concentrations (P=0.73) were seen in TRN as a result of the TP despite significant improvements in VO2max (42.2 ± 1.9 ml•kg-1•min-1, P<0.0001), resting heart rate (P =0.004), BF% (P =0.03) and BMI (P =0.05). No significant changes in CRP, aerobic fitness, BMI or BF% were detected in CON over time. CONCLUSION: Moderate, long-term aerobic training does not appear to affect CRP concentrations in apparently healthy, untrained men despite significant improvements in BW, BF%, BMI, and VO2max.

Background: Alzheimer’s disease, one type of dementia, is predicted to have great impact on society and economy. This effect increases rapidly especially in developing countries. The number of people with Alzheimer’s disease is huge due to the large population in China where the effects of this disease are amplified by the one-child policy. Objective: To review the risk factors of Alzheimer’s disease in different countries and offer some suggestions that how to prevent Alzheimer’s Disease in China that has very limited research on Alzheimer’s disease. To make recommendations for potential strategies to be implemented by policy-makers, government or other stakeholders. Method and results: Relevant studies which identified the risk factors for Alzheimer’s disease and evaluated the interventions and treatments for reducing the risk of getting Alzheimer’s disease, that were published between 1990 and 2012 were searched in PubMed and Google Academic using specific keywords. A total of 1071 studies were found and 62 used. Based on this systematic review, the risk factors of Alzheimer’s disease are age, lifestyle, family history and genetics, vascular, mild cognitive impairment, head injury as well as early-life negative events. There appear to be several important contributions to Alzheimer’s disease prevention including diet, cognitive activity, physical activity, social engagement, smoking cessation, and alcohol ingestion or simply being optimistic. Conclusion: This review has included the potential risk factors of Alzheimer's disease and the ways of preventing Alzheimer's disease, as well as to produce some possible strategies of preventing Alzheimer's disease based on the situation in China for the Chinese government and policy makers such as to use media as an important channel to draw people's attention about Alzheimer's disease and to educate about preventive factors. There should be government-funded education and health services in the rural areas and plans to build more leisure and sports centers in China. The government should also subsidize hospitals and medical centers to provide affordable or even free health examinations for people and build a central database for the purpose of recording, analysis and research into Alzheimer's disease for better understanding of the disease. Medical professionals and volunteers can help to enhance this database by the implementation of data collection to look for symptoms of Alzheimer’s disease. If the patients appear to have such symptoms, further data collection should be taking place, such as family history of Alzheimer’s disease, health status, head injuries, family status, characteristics and behavior, income levels, residential areas and other background information of the patients as part of their work whenever and wherever they go, especially in rural areas. / published_or_final_version / Public Health / Master / Master of Public Health

This dissertation aims at investigating the association between genotypes and phenotypes in human. Both common and rare regulatory variants have been studied. The phenotypes include disease risk, clinical traits and gene expression levels. This dissertation describes three different types of association study. The first study investigated the relationship between common variants and three sub-clinical traits as well as three complex diseases in the Center for Health Discovery and Well Being study (CHDWB). The second study is GWAS analysis of TNF-α and BMI/CRP conducted as a contribution to meta-GWAS analyses of these traits with investigators at the University of Groningen in the Netherlands, and the 1000 Genomes Consortium. The third study was the most original contribution of my thesis as it assessed the association between rare regulatory variants in promoter regions and gene expression levels. The results clearly show an enrichment of rare variants at both extremes of gene expression. This dissertation provides insight into how common and rare variants associate with broadly-defined quantitative phenotypes. The demonstration that rare regulatory variants make a substantial contribution to gene expression variation has important implications for personalized medicine as it implies that de novo and other rare alleles need to be considered as candidate effectors of rare disease risk.

Background: Cardiovascular disease (CVD) is becoming one of the leading causes of death in middle and low income countries, with ischaemic heart disease specifically being predicted to be the 4th and 5th causes respectively. The numerous risk factors for the development of CVD have been extensively researched; however, the same wealth of data is not available for the black South African population as there is for Caucasians. Although the same risk factors that are present in Caucasians have been seen to be present in the black South Africans, there are questions regarding the contributory roles of the individual risk factors, particularly within the context of urbanisation. The role of diet in CVD has been widely studied and it is known that with urbanisation there are dietary changes which are thought to add the development of CVD. With urbanisation, however, there are numerous other lifestyle changes taking place within a population, making it difficult to isolate and make conclusions of the individual role of diet. Added to this is the complex issue of assessing dietary intake. Assessing only nutrient or food intake does not give a holistic picture of dietary habits. The main aim of this study was to determine the association between dietary intake and CVD risk in black South Africans in the context of urbanisation. Methods: The first study that forms part of this thesis was a case-control study aimed at exploring the risk factor profile and clinical presentation of black South African patients with coronary artery disease (CAD). In this study clinical, biochemical and nutrient intakes were compared with a black South African control group that were matched for age and body composition. The second study to form part of this thesis aimed to relate the dietary intakes of the Prospective Urban and Rural Epidemiological (PURE) study population to CVD risk associated with urbanisation, by using both nutrient intake and predefined diet quality scores (DQS). The Healthy Diet Indicator (HDI) and the Deficiency and Excess Score were carefully selected from the large number of available scores and adapted as best as possible for the black South African population. The third study aimed to investigate the role of dietary intake by using nutrients as well as food group consumption patterns as a risk factor in urbanised black South African CAD patients. The dietary habits of the coronary artery disease (CAD) patients were compared to that of an apparently healthy reference group of volunteers selected from the PURE study population. This urbanised reference group was from a similar socio- demographic background and was selected according to their risk for CVD. The Reynolds Risk score which includes C-reactive protein as factor was used to stratify the PURE population into CVD risk categories, in order to select the reference group, which had a low risk (<5%) of developing CVD within the next 10 years. Dietary intake was assessed by comparing nutrient and food group intake (including the ultra-processed food group category). Results and discussion: Black South African CAD patients had increased levels of the same risk factors that are seen in Caucasians with insulin resistance and LDL size being particularly significant in their contribution. Apart from a lower vitamin C intake, no differences in dietary intake and physical activity were observed between the CAD and control group. When comparing the dietary intake of the rural and urban group, the urban group, who had an increased CVD risk, had higher intakes of macro- and micronutrients as well as higher DQS. The DQS must however be interpreted with caution, as when looking at the absolute intakes of individual components of the scores, the urban group was still deficient in a numerous vital micronutrients. A similar picture was seen in the third study, in that the CAD patients also consumed more saturated fatty acids and ultra-processed foods than the reference group, as well as more of the “protective” foods such as fruit and vegetables. However, although their dietary habits could be considered prudent, they were still inadequate in numerous important micronutrients. Conclusion and recommendation: This thesis therefore shows that there are two sides of the story regarding the role of diet in CVD in black South Africans. Although it is important to follow prudent dietary guidelines so as to control the intake of nutrients and foods known to play a role in the development of CVD, it is just as important to ensure adequate intake of the foods rich in micronutrients known to protect against CVD. Dietary advice and prevention programs should also focus on the adequacy aspect of the diet, such as increasing fruit and vegetable and low fat dairy intake, not only on the prudent diet aspect. Additionally, nutrient intake alone does not adequately explain the link between diet and CVD and additional analyses such food consumption patterns are required. / Thesis (PhD (Dietetics))--North-West University, Potchefstroom Campus, 2013

Background: Cardiovascular disease (CVD) is becoming one of the leading causes of death in middle and low income countries, with ischaemic heart disease specifically being predicted to be the 4th and 5th causes respectively. The numerous risk factors for the development of CVD have been extensively researched; however, the same wealth of data is not available for the black South African population as there is for Caucasians. Although the same risk factors that are present in Caucasians have been seen to be present in the black South Africans, there are questions regarding the contributory roles of the individual risk factors, particularly within the context of urbanisation. The role of diet in CVD has been widely studied and it is known that with urbanisation there are dietary changes which are thought to add the development of CVD. With urbanisation, however, there are numerous other lifestyle changes taking place within a population, making it difficult to isolate and make conclusions of the individual role of diet. Added to this is the complex issue of assessing dietary intake. Assessing only nutrient or food intake does not give a holistic picture of dietary habits. The main aim of this study was to determine the association between dietary intake and CVD risk in black South Africans in the context of urbanisation. Methods: The first study that forms part of this thesis was a case-control study aimed at exploring the risk factor profile and clinical presentation of black South African patients with coronary artery disease (CAD). In this study clinical, biochemical and nutrient intakes were compared with a black South African control group that were matched for age and body composition. The second study to form part of this thesis aimed to relate the dietary intakes of the Prospective Urban and Rural Epidemiological (PURE) study population to CVD risk associated with urbanisation, by using both nutrient intake and predefined diet quality scores (DQS). The Healthy Diet Indicator (HDI) and the Deficiency and Excess Score were carefully selected from the large number of available scores and adapted as best as possible for the black South African population. The third study aimed to investigate the role of dietary intake by using nutrients as well as food group consumption patterns as a risk factor in urbanised black South African CAD patients. The dietary habits of the coronary artery disease (CAD) patients were compared to that of an apparently healthy reference group of volunteers selected from the PURE study population. This urbanised reference group was from a similar socio- demographic background and was selected according to their risk for CVD. The Reynolds Risk score which includes C-reactive protein as factor was used to stratify the PURE population into CVD risk categories, in order to select the reference group, which had a low risk (<5%) of developing CVD within the next 10 years. Dietary intake was assessed by comparing nutrient and food group intake (including the ultra-processed food group category). Results and discussion: Black South African CAD patients had increased levels of the same risk factors that are seen in Caucasians with insulin resistance and LDL size being particularly significant in their contribution. Apart from a lower vitamin C intake, no differences in dietary intake and physical activity were observed between the CAD and control group. When comparing the dietary intake of the rural and urban group, the urban group, who had an increased CVD risk, had higher intakes of macro- and micronutrients as well as higher DQS. The DQS must however be interpreted with caution, as when looking at the absolute intakes of individual components of the scores, the urban group was still deficient in a numerous vital micronutrients. A similar picture was seen in the third study, in that the CAD patients also consumed more saturated fatty acids and ultra-processed foods than the reference group, as well as more of the “protective” foods such as fruit and vegetables. However, although their dietary habits could be considered prudent, they were still inadequate in numerous important micronutrients. Conclusion and recommendation: This thesis therefore shows that there are two sides of the story regarding the role of diet in CVD in black South Africans. Although it is important to follow prudent dietary guidelines so as to control the intake of nutrients and foods known to play a role in the development of CVD, it is just as important to ensure adequate intake of the foods rich in micronutrients known to protect against CVD. Dietary advice and prevention programs should also focus on the adequacy aspect of the diet, such as increasing fruit and vegetable and low fat dairy intake, not only on the prudent diet aspect. Additionally, nutrient intake alone does not adequately explain the link between diet and CVD and additional analyses such food consumption patterns are required. / Thesis (PhD (Dietetics))--North-West University, Potchefstroom Campus, 2013

Inflammation contributes to the etiology of type 2 diabetes (T2D) and cardiovascular disease (CVD). Therefore, it is of interest to investigate how diet relates to plasma inflammatory proteins, particularly whole grain and fibre intakes, as these factors have been associated with lower CVD and T2D risk. Only a limited number of observational studies have examined these relationships. The objective of this study was to investigate the cross-sectional relationships of whole and refined grain and dietary fibre intakes with plasma inflammatory proteins. There was a strong inverse relationship between whole grain intake and plasminogen activator inhibitor type 1 (PAI-1) (β =-0.102; SE=0.038; p=0.0077), and a positive relationship between refined grain intake and PAI-1 (β=0.076; SE=0.034; p=0.0251). Additionally, dietary fibre was related to lower concentrations of C-reactive protein (β=-0.034; SE=0.010; p=0.0008) and fibrinogen (β=-1.207; SE=0.505; p=0.0171). This research suggests that whole and refined grain and fibre intakes may influence inflammatory protein concentrations.

Inflammation contributes to the etiology of type 2 diabetes (T2D) and cardiovascular disease (CVD). Therefore, it is of interest to investigate how diet relates to plasma inflammatory proteins, particularly whole grain and fibre intakes, as these factors have been associated with lower CVD and T2D risk. Only a limited number of observational studies have examined these relationships. The objective of this study was to investigate the cross-sectional relationships of whole and refined grain and dietary fibre intakes with plasma inflammatory proteins. There was a strong inverse relationship between whole grain intake and plasminogen activator inhibitor type 1 (PAI-1) (β =-0.102; SE=0.038; p=0.0077), and a positive relationship between refined grain intake and PAI-1 (β=0.076; SE=0.034; p=0.0251). Additionally, dietary fibre was related to lower concentrations of C-reactive protein (β=-0.034; SE=0.010; p=0.0008) and fibrinogen (β=-1.207; SE=0.505; p=0.0171). This research suggests that whole and refined grain and fibre intakes may influence inflammatory protein concentrations.

Background: Premenopausal black women have a 2-3 fold greater rate of coronary heart disease (CHD) than premenopausal white women. The purpose of this study was to provide insight into the reasons for this difference. Methods and Results: We compared CHD risk factors in 100 black and 100 white, healthy premenopausal women age 18-45 years and of relatively advantaged socioeconomic status. Black women consumed diets higher in saturated fat and cholesterol (12% of kcal as saturated fat and 360 mg of cholesterol per day) than did white women (10% of kcal and 290 mg/day) (p=0.008). Black women also had a higher body mass index (BMI) (32.0±9.2 vs. 29.0±9.4 kg/m², p=0.021), and higher systolic (124±17 vs. 115±14 mmHg, p<0.0001), and diastolic (79±14 vs. 75±11 mmHg, p=0.048) blood pressures. The mean plasma Lp(a) concentration was higher in the black women (40.2±31.3 mg/dl) than in the white women (19.2±23.7 mg/dl)(p<0.0001). The black women, however, had lower plasma triglyceride levels (0.91±0.46 vs. 1.22±0.60 mmol/L, p<0.0001), and a trend toward higher HDL cholesterol levels (1.37±0.34 vs. 1.29±0.31 mmol/L, p=0.064) than the white women. Plasma total and LDL cholesterol levels were similar. Rates of cigarette smoking and alcohol intake were low and similar between the races. Black women additionally had higher levels of plasma total homocysteine (8.80 vs. 7.81 μmol/L, p=0.013), lower plasma folates (3.52 vs. 5.23 ng/ml, p<0.0001), and higher vitamin B₁₂ levels (522 vs. 417 pg/ml, p<0.0001) than white women. More white women than black women took a multivitamin supplement (42.4% vs. 24.7%, p=0.019). When adjusted for multivitamin use, homocysteine levels did not differ, but plasma folate remained significantly lower in black women. Sixty-eight percent of black women carried the wild-type methylenetetrahydrofolate reductase genotype, 32.0% were heterozygotes, and none were homozygotes. Of the white women, 47.4% were wild-type, 40.3% heterozygotes, and 12.3% homozygotes (p=0.013). Conclusions: Premenopausal black women consumed more saturated fat and cholesterol and had a higher mean body mass index, blood pressure, Lp(a), and plasma total homocysteine levels than white women. These differences in coronary risk factors may explain the higher incidence of CHD in premenopausal black compared to white women. / Graduation date: 1998