Daniel F. Sarpong

Laboratory, Reading Center, and Coordinating Center Data Management Methods in the Jackson Heart Study

Background:Cardiovascular disease (CVD) is the leading cause of death in the United States. In comparison to whites, African-Americans have a higher risk of dying from CVD and have a worse risk factor profile. The Jackson Heart Study (JHS) is designed to investigate the origin and natural history of CVD in African-Americans. Methods:Reading centers for electrocardiograms, echocardiograms, carotid ultrasonograms, pulmonary function tests, and ambulatory blood pressure monitoring provide training for data accrual, quality assurance assessments, and specialized measurements for research objectives. Laboratories adhering to well-established quality assurance programs provide blood and urine analyses, as well as storage of specimens for future assays. A new Coordinating Center was created to perform functions analogous to those of coordinating centers for multisite studies, including protocol development, data management, statistical analyses, and operational support for the study. An established coordinating center serves as a resource to the JHS Coordinating Center, providing assistance in preparing procedure manuals and data collection forms. This group also designed and developed the JHS data management system. Results:This network of specialized research organizations is implementing state- of-the-science methodologies to assess prevalence, progression, and incidence of CVD and subclinical atherosclerosis, and to evaluate a myriad of risk factors. From November 2000 through March 2004, JHS collected 4000 data fields on each of more than 5300 African-American participants. Conclusions:This article describes the roles of specialized research agencies contributing to JHS, and the methodologies being utilized to accumulate study data. A diverse collection of scientific disciplines is required to collect the information needed to meet the objectives of the JHS.

Genetic Differences between the Determinants of Lipid Profile Phenotypes in African and European Americans: The Jackson Heart Study

Genome-wide association analysis in populations of European descent has recently found more than a hundred genetic variants affecting risk for common disease. An open question, however, is how relevant the variants discovered in Europeans are to other populations. To address this problem for cardiovascular phenotypes, we studied a cohort of 4,464 African Americans from the Jackson Heart Study (JHS), in whom we genotyped both a panel of 12 recently discovered genetic variants known to predict lipid profile levels in Europeans and a panel of up to 1,447 ancestry informative markers allowing us to determine the African ancestry proportion of each individual at each position in the genome. Focusing on lipid profiles—HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C), and triglycerides (TG)—we identified the lipoprotein lipase (LPL) locus as harboring variants that account for interethnic variation in HDL-C and TG. In particular, we identified a novel common variant within LPL that is strongly associated with TG (p = 2.7×10−6) and explains nearly 1% of the variability in this phenotype, the most of any variant in African Americans to date. Strikingly, the extensively studied “gain-of-function” S447X mutation at LPL, which has been hypothesized to be the major determinant of the LPL-TG genetic association and is in trials for human gene therapy, has a significantly diminished strength of biological effect when it is found on a background of African rather than European ancestry. These results suggest that there are other, yet undiscovered variants at the locus that are truly causal (and are in linkage disequilibrium with S447X) or that work synergistically with S447X to modulate TG levels. Finally, we find systematically lower effect sizes for the 12 risk variants discovered in European populations on the African local ancestry background in JHS, highlighting the need for caution in the use of genetic variants for risk assessment across different populations.

Pericardial Adipose Tissue, Atherosclerosis, and Cardiovascular Disease Risk Factors: The Jackson Heart Study

OBJECTIVE Pericardial adipose tissue (PAT), a regional fat depot that surrounds the heart, is associated with an unfavorable cardiometabolic risk factor profile. The associations among PAT, cardiometabolic risk factors, and coronary artery calcification (CAC) and abdominal aortic artery calcification (AAC) in African American populations have not been explored. RESEARCH DESIGN AND METHODS A total of 1,414 African Americans (35% men; mean ± SD age 58 ± 11 years) drawn from the Jackson Heart Study (JHS) underwent multidetector computed tomography assessment of abdominal visceral adipose tissue (VAT) and PAT between 2007 and 2009. Cardiometabolic risk factors, CAC, and AAC were examined in relation to increments of PAT and VAT. RESULTS PAT was significantly correlated with BMI, waist circumference, and VAT (r = 0.35, 0.46, and 0.69; all P < 0.0001). PAT (per 1-SD increase) was associated with elevated levels of systolic blood pressure (P < 0.04), fasting glucose, triglycerides, and C-reactive protein and lower levels of HDL (all P values<0.0001). PAT was also associated with metabolic syndrome (odds ratio [OR] 1.89; P < 0.0001), hypertension (1.48; P < 0.0006), and diabetes (1.40; P < 0.04); all associations were diminished after further adjustment for VAT (most P > 0.05). However, the association of PAT with CAC but not with AAC remained significant (OR 1.34 [95% CI 1.10–1.64]; P < 0.004) after multivariable and VAT adjustment. CONCLUSIONS PAT is significantly correlated with most cardiometabolic risk factors and CAC in the JHS cohort. The results suggest that PAT is an important VAT depot that may exert a local effect on the coronary vasculature.

Fine mapping of the association with obesity at the FTO locus in African-derived populations

Genome-wide association studies have identified many common genetic variants that are associated with polygenic traits, and have typically been performed with individuals of recent European ancestry. In these populations, many common variants are tightly correlated, with the perfect or near-perfect proxies for the functional or true variant showing equivalent evidence of association, considerably limiting the resolution of fine mapping. Populations with recent African ancestry often have less extensive and/or different patterns of linkage disequilibrium (LD), and have been proposed to be useful in fine-mapping studies. Here, we strongly replicate and fine map in populations of predominantly African ancestry the association between variation at the FTO locus and body mass index (BMI) that is well established in populations of European ancestry. We genotyped single nucleotide polymorphisms that are correlated with the signal of association in individuals of European ancestry but that have varying degrees of correlation in African-derived individuals. Most of the variants, including one previously proposed as functionally important, have no significant association with BMI, but two variants, rs3751812 and rs9941349, show strong evidence of association (P = 2.58 x 10(-6) and 3.61 x 10(-6) in a meta-analysis of 9881 individuals). Thus, we have both strongly replicated this association in African-ancestry populations and narrowed the list of potentially causal variants to those that are correlated with rs3751812 and rs9941349 in African-derived populations. This study illustrates the potential of using populations with different LD patterns to fine map associations and helps pave the way for genetically guided functional studies at the FTO locus.

The relation of C - reactive protein to chronic kidney disease in African Americans: the Jackson Heart Study

BackgroundAfrican Americans have an increased incidence and worse prognosis with chronic kidney disease (CKD - estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m2) than their counterparts of European-descent. Inflammation has been related to renal disease in non-Hispanic whites, but there are limited data on the role of inflammation in renal dysfunction in African Americans in the community.MethodsWe examined the cross-sectional relation of log transformed C-reactive protein (CRP) to renal function (eGFR by Modification of Diet and Renal Disease equation) in African American participants of the community-based Jackson Heart Studys first examination (2000 to 2004). We conducted multivariable linear regression relating CRP to eGFR adjusting for age, sex, body mass index, systolic and diastolic blood pressure, diabetes, total/HDL cholesterol, triglycerides, smoking, antihypertensive therapy, lipid lowering therapy, hormone replacement therapy, and prevalent cardiovascular disease events. In a secondary analysis we assessed the association of CRP with albuminuria (defined as albumin-to-creatinine ratio > 30 mg/g).ResultsParticipants (n = 4320, 63.2% women) had a mean age ± SD of 54.0 ± 12.8 years. The prevalence of CKD was 5.2% (n = 228 cases). In multivariable regression, CRP concentrations were higher in those with CKD compared to those without CKD (mean CRP 3.2 ± 1.1 mg/L vs. 2.4 ± 1.0 mg/L, respectively p < 0.0001). CRP was significantly associated with albuminuria in sex and age adjusted model however not in the multivariable adjusted model (p > 0.05).ConclusionCRP was associated with CKD however not albuminuria in multivariable-adjusted analyses. The study of inflammation in the progression of renal disease in African Americans merits further investigation.

The socioeconomic gradient of diabetes prevalence, awareness, treatment, and control among African Americans in the Jackson Heart Study.

PURPOSE Little research has focused on the social patterning of diabetes among African Americans. We examined the relationship between socioeconomic status (SES) and the prevalence, awareness, treatment, and control of diabetes among African Americans. METHODS Education, income and occupation were examined among 4,303 participants (2,726 women and 1,577 men). Poisson regression estimated relative probabilities (RP) of diabetes outcomes by SES. RESULTS The prevalence of diabetes was 19.6% in women and 15.9% in men. Diabetes awareness, treatment, and control were 90.0%, 86.8%, and 39.2% in women, respectively, and 88.2%, 84.4%, and 35.9% in men, respectively. In adjusted models, low-income men and women had greater probabilities of diabetes than high-income men and women (RP, 1.94; 95% confidence interval [CI], 1.28-2.92; and RP, 1.35; 95% CI, 1.04-1.74, respectively). Lack of awareness was associated with low education and low occupation in women (RP, 2.28; 95%CI 1.01-5.18; and RP, 2.62; 95% CI, 1.08-6.33, respectively) but not in men. Lack of treatment was associated with low education in women. Diabetes control was not patterned by SES. CONCLUSIONS Diabetes prevalence is patterned by SES, and awareness and treatment are patterned by SES in women but not men. Efforts to prevent diabetes in African Americans need to address the factors that place those of low SES at higher risk.

The Triglyceride/High-Density Lipoprotein Cholesterol Ratio Fails to Predict Insulin Resistance in African-American Women: An Analysis of Jackson Heart Study

BACKGROUND Compared to whites, insulin-resistant African Americans have worse outcomes. Screening programs that could identify insulin resistance early enough for intervention to affect outcome often rely on triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) levels. Racial differences in TG and HDL-C may compromise the efficacy of these programs in African Americans. A recommendation currently exists to use the TG/HDL-C ratio ≥2.0 to predict insulin resistance in African Americans. The validity of this recommendation needs examination. Therefore, our aim was to determine the ability of TG/HDL-C ratio to predict insulin resistance in African Americans. METHODS In 1,903 African Americans [895 men, 1,008 women, age 55 ± 12 years, mean ± standard deviation (SD), range 35-80 years, body mass index (BMI) 31.0 ± 6.4 kg/m(2), range 18.5-55 kg/m(2)] participating in the Jackson Heart Study, a population-based study of African Americans, Jackson, Mississippi tricounty region, insulin resistance was defined by the upper quartile (≥4.43) of homeostasis model assessment of insulin resistance (HOMA-IR). An area under the receiver operating characteristic curve (AUC-ROC) of >0.70 was required for prediction of insulin resistance by TG/HDL-C. The optimal test cutoff was determined by the Youden index. RESULTS HOMA-IR was similar in men and women (3.40 ± 2.03 vs. 3.80 ± 2.46, P = 0.60). Women had lower TG (94 ± 49 vs. 109 ± 65 mg/dL P < 0.001) and TG/HDL-C (1.9 ± 1.4 vs. 2.7 ± 2.1, P < 0.001). For men, AUC-ROC for prediction of insulin resistance by TG/HDL-C was: 0.77 ± 0.01, mean ± standard error (SE), with an optimal cutoff of ≥2.5. For women, the AUC-ROC was 0.66 ± 0.01, rendering an optimal cutoff indefinable. When women were divided in two groups according to age, 35-50 years and 51-80 years, the results did not change. CONCLUSIONS In African-American men, the recommended TG/HDL-C threshold of 2.0 should be adjusted upward to 2.5. In African-American women, TG/HDL-C cannot identify insulin resistance. The Jackson Heart Study can help determine the efficacy of screening programs in African-Americans.

Epidemiology, Heritability and Genetic Linkage of C-Reactive Protein in African-Americans (From the Jackson Heart Study)

C-reactive protein (CRP) has been studied largely in white non-Hispanic cohorts. There is limited information on CRPs range of values, heritability, and relation to cardiovascular disease risk factors in African Americans. The aim of this study was to evaluate the distribution, clinical correlates, heritability, and genetic linkage of log-transformed CRP in participants in the middle-aged to elderly African American cohort in the community-based Jackson Heart Study. The distribution and correlates of CRP were analyzed for the entire study cohort who underwent the first examination (2001 to 2004). Heritability was estimated for the family cohort nested within the larger Jackson Heart Study (246 families, n = 1,317). The relation between CRP and cardiovascular disease risk factors was tested with multivariable stepwise regression analyses. Heritability was estimated using a variance-components method. Linkage analysis was performed using the multipoint variance-components approach. The study sample consisted of 4,919 participants (mean age 55 +/- 13 years, 63% women); the median CRP concentration was 2.7 mg/L. In stepwise models, traditional risk factors explained 23.8% of CRPs variability, with body mass index (partial R(2) = 13.6%) explaining 57.1% of the variability of CRP due to traditional risk factors. The heritability of CRP (adjusted for age, gender, and body mass index) was 0.45. The strongest linkage evidence for CRP was observed on chromosome 11 (11p13 to 11p11.2), with a logarithm of odds score of 2.72. In conclusion, in this large population-based cohort of African Americans, circulating CRP concentration was heritable and associated with several traditional cardiovascular risk factors, particularly body mass index.

The Contribution of Stress to the Social Patterning of Clinical and Subclinical CVD Risk Factors in African Americans: The Jackson Heart Study

It is often hypothesized that psychosocial stress may contribute to associations of socioeconomic position (SEP) with risk factors for cardiovascular disease (CVD). However, few studies have investigated this hypothesis among African Americans, who may be more frequently exposed to stressors due to social and economic circumstances. Cross-sectional data from the Jackson Heart Study (JHS), a large population-based cohort of African Americans, were used to examine the contributions of stressors to the association of SEP with selected cardiovascular (CVD) risk factors and subclinical atherosclerotic disease. Among women, higher income was associated with lower prevalence of hypertension, obesity, diabetes and carotid plaque and lower levels of stress. Higher stress levels were also weakly, albeit positively, associated with hypertension, diabetes, and obesity, but not with plaque. Adjustment for the stress measures reduced the associations of income with hypertension, diabetes and obesity by a small amount that was comparable to, or larger, than the reduction observed after adjustment for behavioral risk factors. In men, high income was associated with lower prevalence of diabetes and stressors were not consistently associated with any of the outcomes examined. Overall, modest mediation effects of stressors were observed for diabetes (15.9%), hypertension (9.7%), and obesity (5.1%) among women but only results for diabetes were statistically significant. No mediation effects of stressors were observed in men. Our results suggest that stressors may partially contribute to associations of SEP with diabetes and possibly hypertension and obesity in African American women. Further research with appropriate study designs and data is needed to understand the dynamic and interacting effects of stressors and behaviors on CVD outcomes as well as sex differences in these effects.

Socioeconomic Position Is Positively Associated With Blood Pressure Dipping Among African-American Adults: The Jackson Heart Study

BACKGROUND Blunted nocturnal blood pressure (NBP) dipping is a significant predictor of cardiovascular events. Lower socioeconomic position (SEP) may be an important predictor of NBP dipping, especially in African Americans (AA). However, the determinants of NBP dipping are not fully understood. METHODS The cross-sectional associations of individual and neighborhood SEP with NBP dipping, assessed by 24-h ambulatory BP monitoring, were examined among 837 AA adults (Mean age: 59.2 ± 10.7 years; 69.2% women), after adjustment for age, sex, hypertension status, body mass index (BMI), health behaviors, office, and 24-h systolic BP (SBP). RESULTS The mean hourly SBP was consistently lower among participants in the highest category of individual income compared to those in the lowest category, and these differences were most pronounced during sleeping hours. The odds of NBP dipping (defined as >10% decline in the mean asleep SBP compared to the mean awake SBP) increased by 31% (95% confidence interval: 13-53%) and 18% (95% confidence interval: 0-39%) for each s.d. increase in income and years of education, respectively, after multivariable adjustment. CONCLUSIONS NBP dipping is patterned by income and education in AA adults even after accounting for known risk factors. These results suggest that low SEP is a risk factor for insufficient NBP dipping in AA.