Browsing by Author "Williams, S.M."
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Item Cardiovascular disease risk factors in Ghana during the rural-to-urban transition: A cross-sectional study(Public Library of Science, 2016) Kodaman, N.; Aldrich, M.C.; Sobota, R.; Asselbergs, F.W.; Poku, K.A.; Brown, N.J.; Moore, J.H.; Williams, S.M.Populations in sub-Saharan Africa are shifting from rural to increasingly urban. Although the burden of cardiovascular disease is expected to increase with this changing landscape, few large studies have assessed a wide range of risk factors in urban and rural populations, particularly in West Africa. We conducted a cross-sectional, population-based survey of 3317 participants from Ghana (≥18 years old), of whom 2265 (57% female) were from a mid-sized city (Sunyani, population ∼250,000) and 1052 (55% female) were from surrounding villages (populations <5000). We measured canonical cardiovascular disease risk factors (BMI, blood pressure, fasting glucose, lipids) and fibrinolytic markers (PAI-1 and t-PA), and assessed how their distributions and related clinical outcomes (including obesity, hypertension and diabetes) varied with urban residence and sex. Urban residence was strongly associated with obesity (OR: 7.8, 95% CI: 5.3-11.3), diabetes (OR 3.6, 95% CI: 2.3-5.7), and hypertension (OR 3.2, 95% CI: 2.6-4.0). Among the quantitative measures, most affected were total cholesterol (+0.81 standard deviations, 95% CI 0.73-0.88), LDL cholesterol (+0.89, 95% CI: 0.79-0.99), and t-PA (+0.56, 95% CI: 0.48-0.63). Triglycerides and HDL cholesterol profiles were similarly poor in both urban and rural environments, but significantly worse among rural participants after BMI-adjustment. For most of the risk factors, the strength of the association with urban residence did not vary with sex. Obesity was a major exception, with urban women at particularly high risk (26% age-standardized prevalence) compared to urban men (7%). Overall, urban residents had substantially worse cardiovascular risk profiles, with some risk factors at levels typically seen in the developed world.Item Combinations of variations in multiple genes are associated with hypertension(Hypertension, 2000-07) Williams, S.M.; Addy, J.H.; Phillips III, J.A.; Dai, M.; Kpodonu, J.; Afful, J.; Jackson, H.; Joseph, K.; Eason, F.; Murray, M.M.; Epperson, P.; Aduonum, A.; Wong, L.-J.; Jose, P.A.; Felder, R.A.The genetic analysis of hypertension has revealed complex and inconsistent results, making it difficult to draw clear conclusions regarding the impact of specific genes on blood pressure regulation in diverse human populations. Some of the confusion from previous studies is probably due to undetected gene-gene interactions. Instead of focusing on the effects of single genes on hypertension, we examined the effects of interactions of alleles at 4 candidate loci. Three of the loci are in the renin-angiotensin- system, angiotensinogen, ACE, and angiotensin II type 1 receptor, and they have been associated with hypertension in at least 1 previous study. The fourth locus studied is a previously undescribed locus, named FJ. In total, 7 polymorphic sites at these loci were analyzed for their association with hypertension in 51 normotensive and 126 hypertensive age-matched individuals. There were no significant differences between the 2 phenotypic classes with respect to either allele or genotype frequencies. However, when we tested for nonallelic associations (linkage disequilibrium), we found that of the 120 multilocus comparisons, 16 deviated significantly from random in the hypertensive class, but there were no significant deviations in the normotensive group. These findings suggest that genetic interactions between multiple loci rather than variants of a single gene underlie the genetic basis of hypertension in our study subjects. We hypothesize that such interactions may account for the inconsistent findings in previous studies because, unlike our study, prior studies almost always examined single-locus effects and did not consider the effects of variation at other potentially interacting loci.Item Conserved worldwide linkage disequilibrium in the human factor XI gene(Genomics, 2000-12) Tarumi, T.; Martincic, D.; Whitlock, J.A.; Addy, J.H.; Williams, S.M.; Gailani, D.We have identified, in four diverse human populations, five common single-nucleotide polymorphisms (SNPs) in the coding region of the gene for the blood coagulation protease factor XI. Each SNP has an allele frequency > 5% in at least one population. Three of the SNPs (C472T, A844G, and T1234C), spread out over approximately 10 kb of genomic DNA, are in marked linkage disequilibrium (LD) With one another (P < 10-4). Interestingly, haplotypes associated with the linked SNPs are conserved across all populations studied, despite significantly different allele frequencies between populations. The presence of such common, widely dispersed haplotypes could complicate the interpretation of LD studies and emphasizes the need for a better understanding of general patterns of LD to facilitate identification of genes for common disorders. (C) 2000 Academic Press.Item Epistatic interactions in genetic regulation of t-PA and PAI-1 levels in a Ghanaian population(Public Library of Science, 2011) Penrod, N.M.; Poku, K.A.; Vaughn, D.E.; Asselbergs, F.W.; Brown, N.J.; Moore, J.H.; Williams, S.M.The proteins, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1), act in concert to balance thrombus formation and degradation, thereby modulating the development of arterial thrombosis and excessive bleeding. PAI-1 is upregulated by the renin-angiotensin system (RAS), specifically by angiotensin II, the product of angiotensin converting enzyme (ACE) cleavage of angiotensin I, which is produced by the cleavage of angiotensinogen (AGT) by renin (REN). ACE indirectly stimulates the release of t-PA which, in turn, activates the corresponding fibrinolytic system. Single polymorphisms in these pathways have been shown to significantly impact plasma levels of t-PA and PAI-1 differently in Ghanaian males and females. Here we explore the involvement of epistatic interactions between the same polymorphisms in central genes of the RAS and fibrinolytic systems on plasma t-PA and PAI-1 levels within the same population (n = 992). Statistical modeling of pairwise interactions was done using two-way ANOVA between polymorphisms in the ETNK2, RENIN, ACE, PAI-1, t-PA, and AGT genes. The most significant interactions that associated with t-PA levels were between the ETNK2 A6135G and the REN T9435C polymorphisms in females (p = 0.006) and the REN T9435C and the TPA I/D polymorphisms (p = 0.005) in males. The most significant interactions for PAI-1 levels were with REN T9435C and the TPA I/D polymorphisms (p = 0.001) in females, and the association of REN G6567T with the TPA I/D polymorphisms (p = 0.032) in males. Our results provide evidence for multiple genetic effects that may not be detected using single SNP analysis. Because t-PA and PAI-1 have been implicated in cardiovascular disease these results support the idea that the genetic architecture of cardiovascular disease is complex. Therefore, it is necessary to consider the relationship between interacting polymorphisms of pathway specific genes that predict t-PA and PAI-1 levels.Item Male-female differences in the genetic regulation of t-PA and PAI-1 levels in a Ghanaian population(Human Genetics, 2008-11) Schoenhard, J.A.; Asselbergs, F.W.; Poku, K.A.; Stocki, S.A.; Gordon, S.; Vaughan, D.E.; Brown, N.J.; Moore, J.H.; Williams, S.M.Tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) directly influence thrombus formation and degradation, and have been identified as risk factors for thromboembolic disease. Prior studies investigated determinants of t-PA and PAI-1 expression, but mainly in Caucasian subjects. The aim of this study was to identify the contributions of genetic and other factors to inter-individual variation in plasma levels of t-PA and PAI-1 in a large-scale population-based sample from urban West Africa. t-PA, PAI-1 and several demographic, anthropometric, and metabolic parameters were measured in 992 residents of Sunyani, the capital of the Brong-Ahafo region of Ghana. In addition, nine gene polymorphisms associated with components of the renin-angiotensin and fibrinolytic systems were determined. We found that BMI, systolic and diastolic blood pressure, total cholesterol, glucose, and triglycerides were all significant predictors of t-PA and PAI-1 in both females and males. In addition, a significant relationship was found between the PAI-1 4G/5G (rs1799768) polymorphism on PAI-1 levels in females, the TPA I/D (rs4646972) polymorphism on t-PA and PAI-1 in males, the renin (rs3730103) polymorphism on t-PA and PAI-1 in males, the ethanolamine kinase 2 (rs1917542) polymorphism on PAI-1 in males, and the renin (rs1464816) polymorphism on t-PA in females and on PAI-1 in males. This study of urban West Africans shows that t-PA and PAI-1 levels are determined by both genetic loci of the fibrinolytic and renin-angiotensin systems and other factors often associated with cardiovascular disease, and that genetic factors differ between males and females. © Springer-Verlag 2008.Item Multilocus analysis of hypertension: A hierarchical approach(Human Heredity, 2004-02) Williams, S.M.; Ritchie, M.D.; Phillips III, J.A.; Dawson, E.; Prince, M.; Dzhura, E.; Willis, A.; Semenya, A.; Summar, M.; White, B.C.; Addy, J.H.; Kpodonu, J. et.al.While hypertension is a complex disease with a well-documented genetic component, genetic studies often fail to replicate findings. One possibility for such inconsistency is that the underlying genetics of hypertension is not based on single genes of major effect, but on interactions among genes. To test this hypothesis, we studied both single locus and multilocus effects, using a case-control design of subjects from Ghana. Thirteen polymorphisms in eight candidate genes were studied. Each candidate gene has been shown to play a physiological role in blood pressure regulation and affects one of four pathways that modulate blood pressure: vasoconstriction (angiotensinogen, angiotensin converting enzyme - ACE, angiotensin II receptor), nitric oxide (NO) dependent and NO independent vasodilation pathways and sodium balance (G protein-coupled receptor kinase, GRK4). We evaluated single site allelic and genotypic associations, multilocus genotype equilibrium and multilocus genotype associations, using multifactor dimensionality reduction (MDR). For MDR, we performed systematic reanalysis of the data to address the role of various physiological pathways. We found no significant single site associations, but the hypertensive class deviated significantly from genotype equilibrium in more than 25% of all multilocus comparisons (2,162 of 8,178), whereas the normotensive class rarely did (11 of 8,178). The MDR analysis identified a two-locus model including ACE and GRK4 that successfully predicted blood pressure phenotype 70.5% of the time. Thus, our data indicate epistatic interactions play a major role in hypertension susceptibility. Our data also support a model where multiple pathways need to be affected in order to predispose to hypertension. Copyright © 2004 S. Karger AG, Basel.Item A population-based study in Ghana to investigate inter-individual variation in plasma t-PA and PAI-1(Ethnicity and Disease, 2007-02) Williams, S.M.; Stocki, S.; Jiang, L.; Brew, K.; Gordon, S.; Vaughan, D.E.; Brown, N.J.; Poku, K.A.; Moore, J.H.Introduction: Susceptibility to arterial thrombosis has a significant genetic component that is partly due to the expression of two proteins, tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1), that directly influence thrombus formation and degradation. We have initiated a large-scale population-based study to characterize the genetic architecture of plasma t-PA and PAI-1 in Blacks from Sunyani, Ghana. Design: The design of the study is based on the recruitment of 2000 unrelated subjects who are ascertained without regard to chronic disease status. The analyses of the results will be done by dividing the data into two parts, a modeling set and a validation data set. This study design will facilitate the identification of genetic, environmental, and demographic factors that contribute to inter-individual variation in plasma levels of t-PA and PAI-1 in the population at-large. Results: We report the specifics of the study design, as well as phenotype information on the first 1000 subjects. Our results show that females and males differ significantly in several key measures, including PAI-1, BMI, total cholesterol, and systolic blood pressure. Conclusions: The data collected from this population-based study demonstrate significant sex differences in PAI-1 and critical factors that may influence risk of thrombosis. These samples will serve to inform the genetic analyses of t-PA and PAI- levels.