Determinants of mortality status and population attributable risk fractions of the North West Province, South African site of the international PURE study.

BACKGROUND: Mortality data and comparative risk assessments from sub-Saharan Africa are limited. There is an urgent need for high quality population health surveys to be conducted, to improve the national health surveillance system. Our aim was to perform a comparative risk assesment and report on the mortality status and cause of death data of participants from a South African site of the international Prospective Urban Rural Epidemiology study. METHODS: 1 921 Black participants were included, with a median observational time of 13 years resulting in 21 525 person-years. We performed a comparative risk assessment considering four health status domains: locality (rural vs. urban), socio-economic status (SES) (education and employment), lifestyle factors (physical activity, smoking and alcohol consumption) and prevalent diseases (human immunodeficiency virus (HIV), type 2 diabetes mellitus and hypertension). Next, population-attributable fractions (PAFs) were calculated to determine the mortality risk attributable to modifiable determinants. RESULTS: 577 all-cause deaths occurred. Infectious diseases (28.1% of all deaths) were the most frequent cause of death, followed by cardiovascular disease (CVD) (22.4%), respiratory diseases (11.6%) and cancer (11.1%). The three main contributors to all-cause mortality were HIV infection, high SES and being underweight. HIV infection and underweight were the main contributors to infectious disease mortality and hypertension, the urban environment, and physical inactivity to CVD mortality. HIV had the highest PAF, followed by physical inactivity, alcohol and tobacco use and hypertension (for CVD mortality). CONCLUSION: This African population suffers from a quadruple burden of disease. Urban locality, high SES, prevalent disease (HIV and hypertension) and lifestyle factors (physical inactivity, tobacco and alcohol use) all contributed in varying degrees to all-cause and cause-specific mortalities. Our data confirm the public health importance of addressing HIV and hypertension, but also highlights the importance of physical inactivity, tobacco use and alcohol consumption as focal points for public health strategies to produce the most efficient mortality reduction outcomes.

Strategies of Modelling Incident Outcomes Using Cox Regression to Estimate the Population Attributable Risk.

When the Cox model is applied, some recommendations about the choice of the time metric and the model's structure are often disregarded along with the proportionality of risk assumption. Moreover, most of the published studies fail to frame the real impact of a risk factor in the target population. Our aim was to show how modelling strategies affected Cox model assumptions. Furthermore, we showed how the Cox modelling strategies affected the population attributable risk (PAR). Our work is based on data collected in the North-West Province, one of the two PURE study centres in South Africa. The Cox model was used to estimate the hazard ratio (HR) of mortality for all causes in relation to smoking, alcohol use, physical inactivity, and hypertension. Firstly, we used a Cox model with time to event as the underlying time variable. Secondly, we used a Cox model with age to event as the underlying time variable. Finally, the second model was implemented with age classes and sex as strata variables. Mutually adjusted models were also investigated. A statistical test to the multiplicative interaction term the exposures and the log transformed time to event metric was used to assess the proportionality of risk assumption. The model's fitting was investigated by means of the Akaike Information Criteria (AIC). Models with age as the underlying time variable with age and sex as strata variables had enhanced validity of the risk proportionality assumption and better fitting. The PAR for a specific modifiable risk factor can be defined more accurately in mutually adjusted models allowing better public health decisions. This is not necessarily true when correlated modifiable risk factors are considered.

Certain Associations Between Iron Biomarkers and Total and γ' Fibrinogen and Plasma Clot Properties Are Mediated by Fibrinogen Genotypes.

Introduction: Evidence for the relationship between body iron and cardiovascular disease (CVD) is inconsistent and mechanisms involved remain poorly understood. Therefore, we first investigated whether there are linear or non-linear relationships between iron status and total and γ' fibrinogen as well as plasma fibrin clot properties and, second, determined whether there are interactions with iron biomarkers and fibrinogen and FXIII single nucleotide polymorphisms (SNPs) in relation to fibrinogen concentration and functionality. Methods: In this cross-sectional analysis of 2,010 apparently healthy Black South Africans we quantified total and γ' fibrinogen, serum iron, ferritin and transferrin using standardized methods and calculated transferrin saturation (TS). Clot architecture and lysis were explored with a global analytical turbidity assay. The SNPs were determined through an Illumina BeadXpress® platform. Results: Total, but not %γ', fibrinogen negatively correlated with serum iron concentrations, although both decreased over iron tertiles. %γ' fibrinogen correlated negatively with transferrin and decreased over the transferrin tertiles. A weak negative association between total fibrinogen and TS was detected with fibrinogen decreasing over the TS tertiles and categories based on TS. Lag time correlated positively with transferrin and increased over transferrin tertiles, when adjusting for fibrinogen. Before adjusting for fibrinogen, lag time was shorter in those with adequate iron status based on TS than other iron subcategories. Clot lysis time (CLT) negatively correlated with ferritin and was longer in the first than in the third ferritin tertile. Among iron status categories based on ferritin, only CLT differed and was longer in those with adequate iron than with iron-overload. CLT negatively correlated with TS, albeit weakly, shortened over the TS tertiles and was shorter in those with adequate iron based on TS categories. Interactions were observed between FGB SNPs and some of the markers of iron status investigated, in relation to the clot properties with the most prominent associations detected in homozygous carriers of the variant alleles for whom increased iron status was more beneficial than for those harboring the wild-type alleles. Iron modulated the influence of the SNPs so that for the majority iron was beneficial in respect of clot properties, but even more so for a minority group harboring specific variant alleles. Conclusion: This is the first large-scale epidemiological study to relate fibrinogen concentration and functionality to markers of iron status and to take genetic factors into consideration. We have detected a relationship between iron biomarkers and fibrinogen as well as clot characteristics that are influenced by the genetic make-up of an individual.

Lifestyle factors associated with the transition from healthy to unhealthy adiposity among black South African adults over 10 years.

BACKGROUND AND AIMS: Obesity is associated with an increasing prevalence of cardiovascular diseases in Africa, but some obese individuals maintain cardiometabolic health. The aims were to track metabolically healthy overweight or obesity (MHO) over 10 years in African adults and to identify factors associated with a transition to metabolically unhealthy overweight or obesity (MUO). METHODS AND RESULTS: The participants were the South African cohort of the international Prospective Urban and Rural Epidemiological study. From the baseline data of 1937 adults, 649 women and 274 men were followed for 10 years. The combined overweight and obesity prevalence of men (19.2%-23.8%, p = .02) and women (58%-64.7%, p < .001), and the prevalence of the metabolic syndrome in all participants (25.4%-40.2%, p < .001) increased significantly. More than a quarter (26.2%) of the women and 10.9% of men were MHO at baseline, 11.4% of women and 5.1% of men maintained MHO over 10 years, while similar proportions (12.3% of women, 4.7% of men) transitioned to MUO. Female sex, age, and total fat intake were positively associated with a transition to MUO over 10 years, while physical activity was negatively associated with the transition. HIV positive participants were more likely to be MHO at follow-up than their HIV negative counterparts. CONCLUSIONS: One in two black adults with BMI ≥25 kg/m2 maintained MHO over 10 years, while a similar proportion transitioned into MUO. Interventions should focus on lower fat intakes and higher physical activity to prevent the transition to MUO.

Comparison of DNA methylation clocks in Black South African men.

Aims: DNA methylation clocks are widely used to estimate biological age, although limited data are available on non-European ethnicities. This manuscript characterizes the behavior of five DNA methylation clocks in 120 older Black South African men. Methods: The age estimation accuracy of the Horvath, Hannum and skin and blood clocks and the relative age-related mortality risk and predicted time to death portrayed by the PhenoAge and GrimAge biomarkers are investigated, respectively. Results: The results confirm the tendency of DNA methylation clocks to underestimate the biological age of older individuals. GrimAge more accurately characterizes biological decline in this African cohort compared with PhenoAge owing to the unique inclusion of smoking-related damage in the GrimAge estimate. Conclusions: Each clock provides a different fraction of information regarding the aging body. It is essential to continue studying under-represented population groups to ensure methylation-derived indicators are robust and useful in all populations.

The Relationship of Circulating Homocysteine with Fibrinogen, Blood Pressure, and Other Cardiovascular Measures in African Adolescents.

OBJECTIVES: To evaluate the associations between homocysteine (Hcy) and cardiovascular health in South African adolescents. STUDY DESIGN: Circulating Hcy concentrations of 172 South African adolescents (105 girls, ages 13 to <18 years) were measured. Anthropometric and cardiovascular factors were also included and cross-sectionally analyzed through general linear models. RESULTS: Hcy correlated positively with body weight (P = .03; after adjusting for multiple testing, it was not regarded as significant) and muscle mass (P = .01), but negatively with fibrinogen concentrations (P = .001). Across Hcy tertiles, blood pressure produced approximating U-shaped curves, with differences between the middle and upper tertiles (all P < .02). Forty percent of the adolescents had elevated blood pressure, of whom 37% fell in the lowest and 38% in the highest Hcy tertiles. Hcy differed between the sexes (with boys having higher Hcy), but not between subgroups based on puberty, weight, stunting, smoking, or alcohol consumption. CONCLUSIONS: Both high and low Hcy could be early contributing risk factors to cardiovascular health. The associations between Hcy and blood pressure suggest that dietary and lifestyle manipulation, to achieve the optimal range of Hcy, may be beneficial in preventing Hcy-related hypertension in adulthood. The inverse relationship between Hcy and fibrinogen remains to be clarified.

Epigenetic age acceleration in the emerging burden of cardiometabolic diseases among migrant and non-migrant African populations: the population based cross-sectional RODAM study.

BACKGROUND: African populations are experiencing health transitions due to rapid urbanization and international migration. However, the role of biological aging in this emerging burden of cardiometabolic diseases (CMD) among migrant and non-migrant Africans is unknown. We aimed to examine differences in epigenetic age acceleration (EAA) as measured by four clocks (Horvath, Hannum, PhenoAge and GrimAge) and their associations with cardiometabolic factors among migrant Ghanaians in Europe and non-migrant Ghanaians. METHODS: Genome-wide DNA methylation (DNAm) data of 712 Ghanaians from cross-sectional RODAM study were used to quantify EAA. We assessed correlation of DNAmAge measures with chronological age, and then performed linear regressions to determine associations of body mass index (BMI), fasting blood glucose (FBG), blood pressure, alcohol consumption, smoking, physical activity, and one-carbon metabolism nutrients with EAA among migrant and non-migrants. We replicated our findings among 172 rural-urban sibling pairs from India migration study and among 120 native South Africans from PURE-SA-NW study. FINDINGS: We found that Ghanaian migrants have lower EAA than non-migrants. Within migrants, higher FBG was positively associated with EAA measures. Within non-migrants, higher BMI, and Vitamin B9 (folate) intake were negatively associated with EAA measures. Our findings on FBG, BMI and folate were replicated in the independent cohorts. INTERPRETATION: Our study shows that migration is negatively associated with EAA among Ghanaians. Moreover, cardiometabolic factors are differentially associated with EAA within migrant and non-migrant subgroups. Our results call for context-based interventions for CMD among transitioning populations that account for effects of biological aging. FUNDING: European Commission.

Methylation vs. Protein Inflammatory Biomarkers and Their Associations With Cardiovascular Function.

DNA methylation data can be used to estimate proportions of leukocyte subsets retrospectively, when directly measured cell counts are unavailable. The methylation-derived neutrophil-to-lymphocyte and lymphocyte-to-monocyte ratios (mdNLRs and mdLMRs) have proven to be particularly useful as indicators of systemic inflammation. As with directly measured NLRs and LMRs, these methylation-derived ratios have been used as prognostic markers for cancer, although little is known about them in relation to other disorders with inflammatory components, such as cardiovascular disease (CVD). Recently, methylation of five genomic cytosine-phosphate-guanine sites (CpGs) was suggested as proxies for mdNLRs, potentially providing a cost-effective alternative when whole-genome methylation data are not available. This study compares seven methylation-derived inflammatory markers (mdNLR, mdLMR, and individual CpG sites) with five conventionally used protein-based inflammatory markers (C-reactive protein, interleukins 6 and 10, tumor-necrosis factor alpha, and interferon-gamma) and a protein-based inflammation score, in their associations with cardiovascular function (CVF) and risk. We found that markers of CVF were more strongly associated with methylation-derived than protein-based markers. In addition, the protein-based and methylation-derived inflammatory markers complemented rather than proxied one another in their contribution to the variance in CVF. There were no strong correlations between the methylation and protein markers either. Therefore, the methylation markers could offer unique information on the inflammatory process and are not just surrogate markers for inflammatory proteins. Although the five CpGs mirrored the mdNLR well in their capacity as proxies, they contributed to CVF above and beyond the mdNLR, suggesting possible added functional relevance. We conclude that methylation-derived indicators of inflammation enable individuals with increased CVD risk to be identified without measurement of protein-based inflammatory markers. In addition, the five CpGs investigated here could be useful surrogates for the NLR when the cost of array data cannot be met. Used in tandem, methylation-derived and protein-based inflammatory markers explain more variance than protein-based inflammatory markers alone.

The association of PAI-1 with 24 h blood pressure in young healthy adults is influenced by smoking and alcohol use: The African-PREDICT study.

BACKGROUND AND AIMS: The association between plasminogen activator inhibitor-1 (PAI-1) and blood pressure is well established, but it is debatable whether raised PAI-1 levels precede or result from raised blood pressure. Furthermore, it is unclear whether this association already exists in the absence of overt hypertension and to what degree it is influenced by health behaviours. Our aim was to investigate the association of 24 h blood pressure with PAI-1 activity (PAI-1act) in a young, healthy cohort, and to assess the influence of alcohol consumption and smoking on these associations. METHODS AND RESULTS: Healthy black and white men and women (aged 20-30 years, n = 1156) were cross-sectionally analysed. Statistical analysis was performed first split by ethnicity and sex and then by alcohol consumption and smoking. Regression analyses adjusted for age revealed positive associations of 24 h blood pressure with PAI-1act in most groups (p < 0.05). In multivariate-adjusted analyses, significance was lost in all groups except black men, who also had higher monocyte chemoattractant protein-1 (MCP-1) and von Willebrand factor antigen (vWFag) compared to white men (both p < 0.001). Analyses in black men, split by self-reported alcohol use and smoking, revealed 24 h blood pressure-PAI-1act associations only in alcohol users (24 h SBP [B = 4.22, p < 0.001], DBP [B = 2.04, p = 0.015] and PP [B = 2.18, p = 0.013]) and smokers (24 h SBP [B = 6.10, p < 0.001] and PP [B = 4.33, p = 0.001]). CONCLUSION: Our findings support a positive association between 24 h blood pressure and PAI-1, particularly in individuals with higher MCP-1 and vWFag levels. Furthermore, smoking and alcohol consumption play an important role in modifying the association between blood pressure and PAI-1.

Diet and sedentary behaviour in relation to cancer survival. A report from the national health and nutrition examination survey linked to the U.S. mortality registry.

BACKGROUND & AIMS: Cancer is the second most common chronic disease and cause of death in the United States. Our aim was to evaluate the associations of sedentary behavior and nutrient intakes with total and cancer-specific mortality among US cancer survivors. METHODS: Data from 2371 cancer survivors collected by the US National Health and Nutrition Examination Survey between 1999 and 2014 were linked to the US mortality registry. Multivariable adjusted Cox proportional hazard models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for all-cause and cancer-specific mortality associated with sedentary time and nutrient intakes. The interaction between time spent on sedentary activities and nutrient intake was evaluated on additive and multiplicative scales. RESULTS: During a median observational period of 5.7 years, 532 total deaths occurred among cancer survivors, of which 180 were cancer-specific. A monotonic increasing linear relationship between time spent sitting and all-cause mortality was observed (HR = 1.15, 95% CI = 1.03, 1.28 per one standard deviation increment). The highest versus the lowest tertiles of intakes of dietary fiber, carotene, niacin, thiamine, riboflavin, vitamin B6, vitamin B12, and vitamin C were inversely associated with all-cause and cancer-specific mortality (HRs = 0.48 to 0.75). The inverse associations with all-cause mortality were more pronounced for combinations of low sedentary behaviour and high intakes of dietary fiber, carotenoids, vitamin B12, and vitamin C. CONCLUSION: Our findings support recommendations for cancer survivors to reduce time spent sedentary and to follow a balanced diet with adequate intakes of dietary fiber and micronutrients.

Replication and expansion of epigenome-wide association literature in a black South African population.

BACKGROUND: DNA methylation is associated with non-communicable diseases (NCDs) and related traits. Methylation data on continental African ancestries are currently scarce, even though there are known genetic and epigenetic differences between ancestral groups and a high burden of NCDs in Africans. Furthermore, the degree to which current literature can be extrapolated to the understudied African populations, who have limited resources to conduct independent large-scale analysis, is not yet known. To this end, this study examines the reproducibility of previously published epigenome-wide association studies of DNA methylation conducted in different ethinicities, on factors related to NCDs, by replicating findings in 120 South African Batswana men aged 45 to 88 years. In addition, novel associations between methylation and NCD-related factors are investigated using the Illumina EPIC BeadChip. RESULTS: Up to 86% of previously identified epigenome-wide associations with NCD-related traits (alcohol consumption, smoking, body mass index, waist circumference, C-reactive protein, blood lipids and age) overlapped with those observed here and a further 13% were directionally consistent. Only 1% of the replicated associations presented with effects opposite to findings in other ancestral groups. The majority of these inconcistencies were associated with population-specific genomic variance. In addition, we identified eight new 450K array CpG associations not previously reported in other ancestries, and 11 novel EPIC CpG associations with alcohol consumption. CONCLUSIONS: The successful replication of existing EWAS findings in this African population demonstrates that blood-based 450K EWAS findings from commonly investigated ancestries can largely be extrapolated to ethnicities for which epigenetic data are not yet available. Possible population-specific differences in 14% of the tested associations do, however, motivate the need to include a diversity of ethnic groups in future epigenetic research. The novel associations found with the enhanced coverage of the Illumina EPIC array support its usefulness to expand epigenetic literature.

Fibrinogen and fibrin: An illustrated review.

Since its discovery over 350 years ago, studies of fibrinogen have revealed remarkable characteristics. Its complex structure as a large (340 kDa) hexameric homodimer supports complex roles in hemostasis and homeostasis. Fibrinogen synthesis is regulated at the transcriptional and translational levels, undergoing both constitutive (basal) secretion from liver, and inducible upregulation in response to inflammatory events. In addition, alternative splicing yields fibrinogen variants with unique properties and contributions to coagulation biochemistry. During coagulation, fibrinogen conversion to fibrin occurs via thrombin-mediated proteolytic cleavage that produces intermediate protofibrils and then mature fibers that provide remarkable biochemical and mechanical stability to clots. Fibrin formation, structure, and stability are regulated by various genetic, biochemical, and environmental factors, allowing for dynamic kinetics of fibrin formation and structure. Interactions between fibrinogen and/or fibrin and plasma proteins and receptors on platelets, leukocytes, endothelial cells, and other cells enable complex functions in hemostasis, thrombosis, pregnancy, inflammation, infection, cancer, and other pathologies. Disorders in fibrinogen concentration and/or function increase risk of bleeding, thrombosis, and infection. This illustrated review covers fundamental aspects of fibrinogen and fibrin biology, biochemistry, biophysics, epidemiology, and clinical applications. Continued efforts to enhance our understanding of fibrinogen and fibrin in these processes are likely to advance treatment and prevention of many human diseases.

Fibrinogen and clot-related phenotypes determined by fibrinogen polymorphisms: Independent and IL-6-interactive associations.

Interleukin-6 (IL-6) induces the expression of fibrinogen, and polymorphic variation within the fibrinogen genes is believed to alter the magnitude of this expression. The identification of the functional relevance of individual fibrinogen single nucleotide polymorphisms (SNPs) has been hindered by the high linkage disequilibrium (LD) reported in the European fibrinogen gene locus. This study investigated two novel and 12 known fibrinogen SNPs of potential functional relevance, in 2010 Tswana individuals known to have low LD. We aimed to identify functional polymorphisms that contribute to clot-related phenotypes and total and γ' fibrinogen concentrations independently and through their interaction with IL-6, by taking advantage of the high fibrinogen and IL-6 concentrations and the low LD reported in black South Africans. Fibrinogen was significantly associated with IL-6, thereby mediating associations of IL-6 with clot formation and structure, although attenuating the association of IL-6 with clot lysis time. None of the common European fibrinogen haplotypes was present in this study population. Putative functional fibrinogen SNPs FGB-rs7439150, rs1800789 (-1420G/A) and rs1800787 (-148C/T) were significantly associated with fibrinogen concentration and altered clot properties, with several associations significantly influenced by IL-6 concentrations. The impact of harbouring several minor fibrinogen SNP alleles on the association of IL-6 and fibrinogen concentration was cumulative, with possession of each additional minor allele showing a stronger relationship of IL-6 with fibrinogen. This was also reflected in differences in clot properties, suggesting potential clinical relevance. Therefore, when investigating the effect of fibrinogen genetics on fibrinogen concentrations and CVD outcome, the possible interactions with modulating factors and the fact that SNP effects seem to be additive should be taken into account.

Association of 25-hydroxyvitamin D and parathyroid hormone with the metabolic syndrome in black South African women.

The relationship between 25 hydroxyvitamin D (25(OH)D), parathyroid hormone (PTH) and metabolic traits appear to differ among ethnicities and may be influenced by obesity. The aim of the study was to examine the association of serum 25(OH)D or PTH with metabolic syndrome (MetS) while controlling for adiposity in black women. Using a cross-sectional study design, 209 urban black women aged ≥ 43 years from the North West Province, South Africa, were included. Multiple regression models were used to explore the relationship between 25(OH)D or PTH and body composition. To explore the association between 25(OH)D or PTH and MetS, a separate variable was created including at least 3 of the MetS criteria, but excluding elevated waist circumference as a diagnostic criterion in a logistic regression model. The majority of the women (69.9%) were overweight or obese and 65.5% of the women had excessive adiposity using the age-specific cut-off points for body fat percentage. All body composition variables were positively associated with PTH, whereas body mass index and waist circumference, but not body fat percentage, had negative associations with 25(OH)D also after adjusting for confounders. Before and after adjusting for age, body fat, habitual physical activity, tobacco use, season of data collection, and estimated glomerular filtration rate, neither 25(OH)D nor PTH showed significant associations with MetS. Although PTH was positively associated and 25(OH)D was negatively associated with adiposity in black women, there was no association between either 25(OH)D or PTH and MetS in this study population, nor did adiposity influence these relationships.

Candidate gene analysis of the fibrinogen phenotype reveals the importance of polygenic co-regulation.

Fibrinogen and its functional aspects have been linked to cardiovascular disease. There is vast discrepancy between the heritability of fibrinogen concentrations observed in twin studies and the heritability uncovered by genome wide association studies. We postulate that some of the missing heritability might be explained by the pleiotropic and polygenic co-regulation of fibrinogen through multiple targeted genes, apart from the fibrinogen genes themselves. To this end we investigated single nucleotide polymorphisms (SNPs) in genes coding for phenotypes associated with total and γ' fibrinogen concentrations and clot properties. Their individual and accumulative associations with the fibrinogen variables were explored together with possible co-regulatory processes as a result of the gain and loss of transcription factor binding sites (TFBS). Seventy-eight SNPs spanning the APOB, APOE, CBS, CRP, F13A1, FGA, FGB, FGG, LDL-R, MTHFR, MTR, PCSK-9 and SERPINE-1 genes were included in the final analysis. A novel PCSK-9 SNP (rs369066144) was identified in this population, which associated significantly (p=0.04) with clot lysis time (CLT). Apart from SNPs in the fibrinogen (FGA, FGB and FGG) and FXIII (F13A1) genes, the fibrinogen phenotypes were also associated with SNPs in genes playing a role in lipid homeostasis (LDL-R, PCSK-9) together with CBS and CRP polymorphisms (particularly, CRP-rs3093068). The genetic risk scores, presenting accumulative genetic risk, were significantly associated (p≤0.007) with total and γ' fibrinogen concentrations, lag time, slope and CLT, highlighting the importance of a polygenetic approach in determining complex phenotypes. SNPs significantly associated with the fibrinogen phenotypes, resulted in a total of 75 TFBS changes, of which 35 resulted in a loss and 40 in a gain of TFBS. In terms of co-regulation, V$IRF4.02, V$E2FF and V$HIFF were of particular importance. The investigation into TFBS provided valuable insight as to how sequence divergences in seemingly unrelated genes can result in transcriptional co-regulation of the fibrinogen phenotypes. The observed associations between the identified SNPs and the fibrinogen phenotypes therefore do not imply direct effects on cardiovascular disease outcomes, but may prove useful in explaining more of the genetic regulation of the investigated fibrinogen phenotypes.

Plasma clot lysis time and its association with cardiovascular risk factors in black Africans.

Studies in populations of European descent show longer plasma clot lysis times (CLT) in patients with cardiovascular disease (CVD) than in controls. No data are available on the association between CVD risk factors and fibrinolytic potential in black Africans, a group undergoing rapid urbanisation with increased CVD prevalence. We investigated associations between known CVD risk factors and CLT in black Africans and whether CLTs differ between rural and urban participants in light of differences in CVD risk.Data from 1000 rural and 1000 urban apparently healthy black South Africans (35-60 years) were cross-sectionally analysed.Increased PAI-1(act), BMI, HbA1c, triglycerides, the metabolic syndrome, fibrinogen concentration, CRP, female sex and positive HIV status were associated with increased CLTs, while habitual alcohol consumption associated with decreased CLT. No differences in CLT were found between age and smoking categories, contraceptive use or hyper- and normotensive participants. Urban women had longer CLT than rural women while no differences were observed for men.CLT was associated with many known CVD risk factors in black Africans. Differences were however observed, compared to data from populations of European descent available in the literature, suggesting possible ethnic differences. The effect of urbanisation on CLT is influenced by traditional CVD risk factors and their prevalence in urban and rural communities.