Biomedical subjects
Publications and source records attributed to Richard S Cooper.
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OBJECTIVES: We compared voluntary participation and comprehension of informed consent among individuals of African ancestry enrolled in similarly designed genetic studies of hypertension in the United States and Nigeria. METHODS: Survey questionnaires were used to evaluate factors associated with voluntariness (the number of people volunteering) and understanding of the study's genetic purpose. A total of 655 individuals (United States: 348; Nigeria: 307) were interviewed after participation in the genetic studies. RESULTS: Most US respondents (99%), compared with 72% of Nigerian respondents, reported being told the study purpose. Fewer than half of the respondents at both sites reported that the study purpose was to learn about genetic inheritance of hypertension. Most respondents indicated that their participation was voluntary. In the United States, 97% reported that they could withdraw, compared with 67% in Nigeria. In Nigeria, nearly half the married women reported asking permission from husbands to enroll in the hypertension study; no respondents sought permission from local elders to participate in the study. CONCLUSIONS: Our findings highlight the need for more effective approaches and interventions to improve comprehension of consent for genetic research among ethnically and linguistically diverse populations in all settings.
We investigated whether isoprostanes, as a marker of lipid peroxidation, may be involved in the development of impaired glucose tolerance (IGT) or diabetes. Using a nested case-control study, we tracked the changes in isoprostane levels, insulin sensitivity (IS) and beta-cell function (BCF) in Afro-Jamaicans who progressed to IGT and diabetes over 3.9 years. Anthropometry, glucose tolerance, insulin levels, blood pressure and urinary isoprostane concentration were measured at baseline and follow-up. IS and BCF were estimated by the method of homeostasis assessment. Fifty-two individuals who progressed to IGT or diabetes and 44 age, sex and body mass index (BMI) matched controls were studied. Progression to glucose intolerance was significantly related with baseline BCF (p< or =0.01), but not isoprostane levels or IS. Glucose concentrations (fasting and 2 h) on follow-up were significantly correlated to baseline IS, baseline BCF, follow-up IS and follow-up BCF (p-values<0.05). In multiple regression analysis, only follow-up IS and BCF (p-values< or =0.001) independently predicted fasting glucose and 2h glucose levels at follow-up. Isoprostanes were not significantly associated with IS or BCF (p-values>0.1). We concluded that isoprostanes may not be causally involved in the development of glucose intolerance, insulin resistance or deteriorating BCF.
The T594M allele of the epithelial sodium channel beta-subunit has been proposed as a gain-of-function mutation leading to salt-sensitive hypertension in blacks that is particularly responsive to the specific sodium channel antagonist amiloride. However, the positive associations derive from small convenience samples, and the amiloride challenge study lacked a control group. We determined whether the T594M allele was associated with hypertension and blood pressure (BP) response to amiloride in 2 well-characterized random population samples including 3137 Dallas County subjects and 1666 Jamaican blacks. In multivariate models, the T594M allele was not predictive of systolic BP (adjusted odds ratio for hypertension 1.1; 95% confidence interval, 0.7 to 1.8). Amiloride treatment did not lower the BP of 6 T594M heterozygotes significantly more than in 22 control subjects (P=0.8). We conclude that the T594M allele does not contribute significantly to BP in blacks and does not predict a significantly superior response to amiloride therapy.
Selected missense mutations in the proprotein convertase subtilisin/kexin type 9 serine protease gene (PCSK9) cause autosomal dominant hypercholesterolemia, whereas nonsense mutations in the same gene are associated with low plasma levels of low-density lipoprotein cholesterol (LDL-C). Here, DNA sequencing and chip-based oligonucleotide hybridization were used to determine whether other sequence variations in PCSK9 contribute to differences in LDL-C levels. The coding regions of PCSK9 were sequenced in the blacks and whites from the Dallas Heart Study (n=3,543) who had the lowest (<5th percentile) and highest (>95th percentile) plasma levels of LDL-C. Of the 17 missense variants identified, 3 (R46L, L253F, and A443T) were significantly and reproducibly associated with lower plasma levels of LDL-C (reductions ranging from 3.5% to 30%). None of the low-LDL-C variants were associated with increased hepatic triglyceride content, as measured by proton magnetic resonance spectroscopy. This finding is most consistent with the reduction in LDL-C being caused primarily by accelerating LDL clearance, rather than by reduced lipoprotein production. Association studies with 93 noncoding single-nucleotide polymorphisms (SNPs) at the PCSK9 locus identified 3 SNPs associated with modest differences in plasma LDL-C levels. Thus, a spectrum of sequence variations ranging in frequency (from 0.2% to 34%) and magnitude of effect (from a 3% increase to a 49% decrease) contribute to interindividual differences in LDL-C levels. These findings reveal that PCSK9 activity is a major determinant of plasma levels of LDL-C in humans and make it an attractive therapeutic target for LDL-C lowering.
A meta-analysis of the results from a multicenter genome-wide linkage study for hypertension and blood pressure (BP) based on an initial sample of 6,245 individuals was published in 2003. We report here a combined linkage analysis of hypertension and BP using the complete Family Blood Pressure Program (FBPP) dataset, which includes a total of 12,028 genotyped individuals. Genome-wide linkage analyses for hypertension and BP were first performed in each of the studied ethnic group within each network and the results were combined with a meta-analysis using a modified Fisher's method of combining P values. Our meta-analysis of genome scans for the latest FBPP dataset reveals suggestive linkage for hypertension and BP at several regions on the human genome. Strong evidence for linkage at two of these regions, 2p14 and 3p14.1, have also been published in previous meta-analyses, making them good candidate locations for susceptibility variants.
BACKGROUND: In many genetic studies of complex traits, sample sizes are often too small to detect linkages of low-to-moderate effects. However, the combined linkage evidence across several studies can be synthesized using meta-analysis with the aim of providing more definitive support of linkage. METHODS: In the current study using the National Heart, Lung, and Blood Institute (NHLBI) GeneLink Project, a meta-analysis based on a modification of Fisher's method of pooling P values was used to investigate linkage for systolic blood pressure (SBP) and diastolic blood pressure (DBP) values across three studies involving African American and Nigerian families (HyperGEN, Health, Risk Factors, Exercise Training and Genetics [HERITAGE], and Genetics of Hypertension in Blacks). RESULTS: The meta results suggest two regions (2p and 7p) provide enhanced linkage evidence compared with the individual study results. The maximal meta Lod score of 2.9 on 2p14-p13.1 (64-78 cM) represented approximately 1-Lod unit increase over the respective individual study scores. This general region has been implicated previously involving primarily families of white ethnicity and provides confirmatory evidence that this QTL is common across ethnic groups. The second finding at 7p21.3-p15.3 (8-25 cM) provided a meta Lod of 3.5. Although region was implicated primarily in the Nigerian subjects the low-level but consistent support involving the African American families (individual Lod score of 1.0) suggests a novel QTL with respect to BP variation in individuals of black ethnicity. CONCLUSIONS: Follow-up studies involving positional cloning efforts of the combined families showing linkage evidence in these regions (particularly 2p) may be warranted to verify these findings and identify the genes and causative variants.
The application of genome-wide linkage scans to uncover susceptibility loci for complex diseases offers great promise for the risk assessment, treatment, and understanding of these diseases. However, for most published studies, linkage signals are typically modest and vary considerably from one study to another. The multicenter Family Blood Pressure Program has analyzed genome-wide linkage scans of over 12 000 individuals. Based on this experience, we developed a protocol for large linkage studies that reduces two sources of data error: pedigree structure and marker genotyping errors. We then used the linkage signals, before and after data cleaning, to illustrate the impact of missing and erroneous data. A comprehensive error-checking protocol is an important part of complex disease linkage studies and enhances gene mapping. The lack of significant and reproducible linkage findings across studies is, in part, due to data quality.
The poorer countries of the world continue to struggle with an enormous health burden from diseases that we have long had the capacity to eliminate. Similarly, the health systems of some countries, rich and poor alike, are fragmented and inefficient, leaving many population groups underserved and often without health care access entirely. Cuba represents an important alternative example where modest infrastructure investments combined with a well-developed public health strategy have generated health status measures comparable with those of industrialized countries. Areas of success include control of infectious diseases, reduction in infant mortality, establishment of a research and biotechnology industry, and progress in control of chronic diseases, among others. If the Cuban experience were generalized to other poor and middle-income countries human health would be transformed. Given current political alignments, however, the major public health advances in Cuba, and the underlying strategy that has guided its health gains, have been systematically ignored. Scientists make claims to objectivity and empiricism that are often used to support an argument that they make unique contributions to social welfare. To justify those claims in the arena of international health, an open discussion should take place on the potential lessons to be learned from the Cuban experience.
BACKGROUND: Pharmacologic control of hypertension is an essential component of the current strategy to control cardiovascular diseases. Much concern has been focused in recent years on the challenge that cardiovascular disease poses for developing countries. Available medical therapies should be equally effective in low- and high-resource settings; however, this has not yet been demonstrated. Cuba has a well-organized primary-care system and has made reduction of cardiovascular diseases a priority, particularly through detection and treatment of hypertension. METHODS: To determine current hypertension control rates a population-based sample of 1667 persons aged 15-74 years was examined in the city of Cienfuegos. RESULTS: The prevalence of hypertension, weighted to the age structure of the sampled population, was 20%. Among all hypertensives, 78% were previously aware of the condition, 61% were currently taking medications, and 40% had systolic/diastolic blood pressures < 140/90 mmHg (men = 29%, women = 49%). Among treated hypertensives, 62% had blood pressures < 140/90 mmHg. DISCUSSION: The level of control documented in this survey is higher than reported previously from population surveys in other countries. If confirmed in broader samples in Cuba, these findings would suggest that effective control of hypertension is highly feasible in low-resource settings.
We explored the power and consistency to detect linkage and association with meta-analysis and pooled data analysis using Genetic Analysis Workshop 14 simulated data. The first 10 replicates from Aipotu population were used. Significant linkage and association was found at all 4 regions containing the major loci for Kofendrerd Personality Disorder (KPD) using both combined analyses although no significant linkage and association was found at all these regions in a single replicate. The linkage results from both analyses are consistent in terms of the significance level of linkage test and the estimate of locus location. After correction for multiple-testing, significant associations were detected for the same 8 single-nucleotide polymorphisms (SNP) in both analyses. There were another 2 SNPs for which significant associations with KPD were found only by pooled data analysis. Our study showed that, under homogeneous condition, the results from meta-analysis and pooled data analysis are similar in both linkage and association studies and the loss of power is limited using meta-analysis. Thus, meta-analysis can provide an overall evaluation of linkage and association when the original raw data is not available for combining.
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OBJECTIVES: An adequate description of the trends in cardiovascular disease (CVD) is not available for most of the developing world. Cuba provides an important exception, and we sought to use available data to offer insights into the changing patterns of CVD there. METHODS: We reviewed Cuban public health statistics, surveys, and reports of health services. RESULTS: CVD has been the leading cause of death since 1970. A 45% reduction in heart disease deaths was observed from 1970 to 2002; the decline in stroke was more limited. There are moderate prevalences of all major risk factors. CONCLUSIONS: The Cuban medical care system has responded vigorously to the challenge of CVD; levels of control of hypertension are the highest in the world. Nonindustrialized countries can decisively control CVD.
BACKGROUND: The natriuretic peptide system contributes to blood pressure regulation. Atrial and brain natriuretic peptides are cleaved into smaller biologically active molecules by corin, a transmembrane serine protease expressed in cardiomyocytes. METHOD AND RESULTS: This genotype-phenotype genetic association study included replication samples and genomic control to correct for population stratification. Sequencing of the human corin gene identified 2 nonsynonymous, nonconservative single nucleotide polymorphisms (Q568P and T555I) in near-complete linkage disequilibrium, thus describing a single minor I555 (P568) corin gene allele. This allele was present in the heterozygote state in &12% of blacks but was extremely rare in whites (<0.5% were homozygous for the minor allele). In our primary population sample, the Dallas Heart Study, after adjustment for potential confounders, including population stratification, the corin I555 (P568) allele remained independently associated with increased risk for prevalent hypertension (odds ratio, 1.63; 95% CI, 1.11 to 2.38; P=0.013). The corin I555 (P568) allele also was associated with higher systolic blood pressure in subjects not using antihypertensive medication in unadjusted (133.7+/-20.7 versus 129.4+/-17.4 mm Hg; P=0.029) and adjusted (132.5+/-1.6 versus 128.9+/-0.6 mm Hg; P=0.029) analyses. The independent association of the minor corin allele with increased risk for prevalent hypertension was confirmed in the Multi-Ethnic Study of Atherosclerosis (odds ratio, 1.50; 95% CI, 1.09 to 2.06; P=0.014). In addition, the association of the minor corin I555 (P568) allele with higher systolic blood pressure was confirmed in adjusted analysis in the Chicago Genetics of Hypertension Study (125.8+/-1.9 versus 121.4+/-0.7 mm Hg; P=0.03). CONCLUSIONS: The corin I555 (P568) allele is common in blacks and is associated with higher blood pressure and an increased risk for prevalent hypertension.
The causes of variation in hypertension risk by ethnicity and educational level are not well understood. To gain further insight into this issue in a nonindustrialized country, a population-based sample of 1,667 persons aged 15-74 years was recruited in Cienfuegos, Cuba. In this 2001-2002 study, interviewers classified 29% of participants as Black or mulatto and 71% as White. Educational attainment was stratified at the median number of school years. Compared with White women, non-White women had higher blood pressures (3.0/1.7, systolic blood pressure/diastolic blood pressure) and a higher prevalence of hypertension (24%, 95% confidence interval: 20, 28 vs. 15%, 95% confidence interval: 12, 18). Among men, no differences in blood pressure were observed by ethnicity. Men with a lower level of education had a 14% lower risk of hypertension compared with men above the median. However, women with a lower level of education had a 24% increase in risk. The effect of education was equally strong among Whites alone and when occupation was used for stratification. No variation was observed for body mass index or self-reported health behaviors by ethnicity or education. The narrower ethnic gradient in hypertension prevalence than seen in North America and the gender-specific social status effect, in the context of relatively equal living conditions, suggest that the influence of psychosocial stressors may be specific to cultural contexts.
Although recent studies have suggested that blacks compared with whites have an increased prevalence of left ventricular hypertrophy, it remains uncertain whether this is true despite adjustment for body composition (fat mass and fat-free mass) and when assessed by cardiac MRI in the general population. The Dallas Heart Study is a population-based study of Dallas County in which 1335 black and 858 white participants 30 to 67 years of age underwent detailed assessment including dual-energy x-ray absorptiometry scan to measure body composition and cardiac MRI. Left ventricular hypertrophy, whether defined by indexation to body surface area (P<0.001), fat-free mass (P=0.002), or height2.7 (P<0.001) was 2- to 3-fold more common in black versus white women. Similar results were seen when comparing black and white men (P<0.001 when left ventricular hypertrophy was indexed to body surface area or height2.7 and P=0.05 when indexed to fat-free mass). Ethnic disparities in left ventricular mass persisted in multivariable models despite adjustment for fat mass, fat-free mass, systolic blood pressure, age, gender, and measures of socioeconomic status. We conclude that blacks compared with whites have increased left ventricular mass and a 2- to 3-fold higher prevalence of left ventricular hypertrophy in the general population, as assessed by cardiac MRI. The ethnic differences in left ventricular mass are independent of differences in body composition.
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