Soluble Urokinase Plasminogen Activator Receptor : exploring its potential as a marker of cardiovascular disease development in black South Africans of the PURE study
Motivation - In South Africa, various transitional changes parallel detrimental modifications in lifestyle behaviour of especially the lower socio-economic communities. We are currently double-burdened by a high prevalence of communicable and noncommunicable diseases such as diabetes, chronic respiratory and cardiovascular diseases, which is accompanied by a high cardiovascular mortality rate. Healthcare and treatment resources are limited and low-cost intervention strategies to lower this burden are urgently needed. Unhealthy lifestyle behaviours, such as excessive alcohol consumption and tobacco use, are known to augment inflammation as reflected by inflammatory markers such as C-reactive protein and interleukin-6, which are well-known risk factors for cardiovascular disease and mortality. Several studies showed the prognostic value of soluble urokinase plasminogen activator receptor (suPAR) in advanced disease states and that suPAR associates with different types of cancers, infectious diseases, diabetes, coronary artery disease and all-cause mortality. Since the discovery of suPAR in 1991, the role of this less known inflammatory marker in various diseases has been under debate. It was further reported that black individuals have higher suPAR levels than whites. However, whether an unhealthy lifestyle and cardiometabolic risk factors are related to suPAR, whether suPAR plays a role in the development of cardiovascular disease such as hypertension, and whether suPAR could predict all-cause and cardiovascular mortality, especially among the understudied black South African population, remain to be established. Aim - The central aim of this thesis was to determine if suPAR associates with cardiovascular disease development in a black South African population. We therefore explored whether suPAR relates to lifestyle and cardiometabolic risk factors, associates with the development of hypertension and has prognostic value for cardiovascular and all-cause mortality over five years. Methodology - This five-year prospective sub-study, which is embedded in the international Prospective Urban and Rural Epidemiology study, included black South African volunteers of ages older than 35 years from the North West province, South Africa. Baseline data collection took place in 2005 during which 2 010 men and women from urban and rural areas were examined. A total of 1 292 participants returned for examination and were followed-up for the first time in 2010. Of these participants, 214 were newly identified as being infected with the human immunodeficiency virus (HIV), while 233 died during the five year period. Standardised methods were used to capture all data and included health questionnaires (lifestyle factors, medication use, disease status and history, mortality outcome), cardiovascular and anthropometric measurements, as well as biochemical analyses of inflammatory markers (suPAR, C-reactive protein, interleukin-6), HIV status and relevant metabolic markers. In preparation for statistical analyses, non-Gaussian variables were logarithmically transformed. We compared means and proportions with independent t-tests, analysis of variance, analysis of covariance (for adjustments) and Chi-square tests, while dependent t-tests and McNemar tests were used for analysis of longitudinal data within individual groups. We determined relationships between variables with Pearson’s correlation coefficients. Independent relationships were determined with logistic regression, forward stepwise multiple regression and proportional Cox-regression analyses. Mortality rates were calculated using Kaplan-Meier survival function estimates and log-rank tests. In all cases, p≤0.05 were used to indicate statistical significance. Results and conclusions of each manuscript Three manuscripts were written in order to achieve the aim of this thesis. In the first manuscript we explored the cross-sectional relationships of suPAR with lifestyle and cardiometabolic risk factors in a black South African population. We showed that suPAR was independently associated with lifestyle behaviours, including alcohol consumption, as indicated by gamma-glutamyltransferase levels (β=0.24; p<0.001), tobacco use (β=0.13; p<0.001) and unemployment (β=0.07; p=0.039), despite no direct links with cardiometabolic factors such as blood pressure, dyslipidaemia, glycaemia or adiposity. These findings emphasise the important need to address lifestyle behaviours in order to limit the detrimental effect of modifiable risk factors on the health and mortality rate of this population. Secondly, we determined whether suPAR was associated with the development of hypertension over five years. We found that suPAR was higher and increased more prominently (14.2% vs. 6.94%; p=0.007) in participants that developed hypertensio than in those that remained normotensive. Change in systolic blood pressure was independently associated with baseline suPAR (β=0.14; p=0.043), while becoming hypertensive was associated with an increase in suPAR (odds ratio=1.41; p=0.015). Whether inflammation leads to the development of hypertension or vice versa, remains unclear. Our findings emphasise the need to acknowledge the role of inflammation in hypertension and may permit further investigation of the use of suPAR as a potential marker for early risk identification and intervention. The third manuscript investigated the prognostic value of suPAR, compared to other inflammatory markers C-reactive protein and interleukin-6, in all-cause and cardiovascular mortality. We showed for the first time in a black population that suPAR predicted both all-cause (hazard ratio=1.27; p=0.003) and cardiovascular mortality (hazard ratio=1.40; p=0.026), independent of interleukin-6. Future research is needed to clarify the mechanisms behind the association of suPAR with cardiovascular mortality and to explore the possibility of a suPAR cut-off value for early identification of those with increased risk for cardiovascular morbidity and mortality in this population. General conclusion - In this thesis we showed for the first time that suPAR has potential as a marker of cardiovascular disease development in black South Africans. SuPAR associated with hypertension and independently predicted all-cause and cardiovascular mortality over five years. Our findings, that suPAR is independently associated with adverse health behaviours such as alcohol and tobacco use, lend support for the use of suPAR as a novel approach for early risk identification and intervention strategies, which may be effective in combatting the high cardiovascular disease burden among the black South African community.
- Health Sciences