Population-based Cohort Of African Americans Research Articles

Abstract 25: Epigenome-Wide DNA Methylation Analysis Reveals Novel Hematologic Trait Associations for African Americans in The Jackson Heart Study

Cardiovascular disease (CVD) is the leading cause of death in the U.S. and disproportionately affects African Americans (AAs). Routinely measured circulating red blood cell traits, which are highly heritable and differ by ethnicity, are independent predictors for CVD-related traits including hypertension, stroke, coronary heart disease, and CVD mortality. Many genetic loci associated with red blood cell count (RBC), hemoglobin (HGB), hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and red cell distribution width (RDW) have been identified. However, identified genetic variants do not fully explain the heritability of these traits. Epigenetic alterations in DNA methylation likely also explain a portion of red cell trait variance, and detecting methylation quantitative trait loci (meQTLs) can provide critical insight into the development of CVD and CVD health disparities. We performed an epigenome-wide association analysis to identify CpG sites at which DNA methylation levels are associated with red blood cell traits in 1753 participants from the Jackson Heart Study, a population-based cohort of AAs. DNA methylation was measured by the Illumina MethylationEPIC array, interrogating approximately 850,000 CpG sites in peripheral blood mononuclear cells at the baseline exam. Associations were assessed using linear mixed models adjusted for age, sex, cell proportions, genetic ancestry, and experimental batch effects. A Bonferroni-corrected p-value of 9x10 -8 was used to assess statistical significance. We identified many significant differentially methylated CpG sites associated with red blood cell traits. Analysis of RBC, HGB, MCV, MCH, and MCHC revealed a novel highly significant association with a CpG annotated to a non-coding RNA (cg11703701; RBC P = 5.19x10 -22 , HGB P = 1.19x10 -11 , MCV P = 4.69x10 -59 , MCH P = 2.68x10 -67 , MCHC P = 2.32x10 -31 ), as well as a strong signal for a reprogramming-specific differentially methylated region (cg04321267; RBC P = 1.67x10 -16 , HGB P = 3.58x10 -12 , MCV P = 2.12x10 -49 , MCH P = 1.74x10 -57 , MCHC P = 5.91x10 -30 ). Multiple CpGs annotated to genes HBA1 and HBA2 were associated with RBC, MCV, MCH, and MCHC, while ITPKB (cg23740281; HGB P = 4.88x10 -10 , HCT P = 6.20x10 -11 ) and ALDH2 (cg17969951; HGB P = 3.03x10 -11 , HCT P = 8.31x10 -9 ) were significantly associated with both HGB and HCT. Additional CpG sites were significantly associated with HCT ( PLXND1 cg22902177; P = 7.54x10 -11 and ARL1 cg23903357; P = 9.86x10 -11 ) and RDW ( CPNE2 cg09018739; P = 3.03x10 -22 ). These findings shed light on potential hematologic and CVD mechanisms in understudied populations. Future work will explore the role of neighboring SNPs in mediating observed methylation-trait associations, and replicate results in an additional multi-ethnic cohort.

Psychosocial correlates of apparent treatment-resistant hypertension in the Jackson Heart Study.

Apparent treatment-resistant hypertension (aTRH) is associated with adverse cardiovascular outcomes. aTRH is common and disproportionately affects African Americans. The objective of this study is to explore psychosocial correlates of aTRH in a population-based cohort of African Americans with hypertension. The sample included 1392 participants in the Jackson Heart Study with treated hypertension who reported being adherent to their antihypertensive medications. aTRH was defined as uncontrolled clinic BP (⩾140/90 mm Hg) with ⩾3 classes of antihypertensive medication or treatment with ⩾4 classes of antihypertensive medication, including a diuretic. Self-reported medication adherence was defined as taking all prescribed antihypertensive medication in the 24 h before the study visit. The association of psychosocial factors (chronic stress, depressive symptoms, perceived social support and social network) with aTRH was evaluated using Poisson regression with progressive adjustment for demographic, clinical and behavioural factors. The prevalence of aTRH was 15.1% (n=210). Participants with aTRH had lower social network scores (that is, fewer sources of regular social contact) compared with participants without aTRH (P<0.01). No other psychosocial factors differed between groups. Social network was also the only psychosocial factor that was associated with aTRH prevalence in regression analyses. In age-, sex-adjusted and fully adjusted models, one additional unique source of social contact was associated with a 19% (PR=0.81; 95% confidence interval (CI): 0.68-0.94, P=0.001) and a 13% (PR=0.87; 95% CI 0.74-1.0, P=0.041) lower prevalence of aTRH, respectively. Social network was independently associated with aTRH and warrants further investigation as a potentially modifiable determinant of aTRH in African Americans.

Prevalence, Determinants, and Clinical Significance of Masked Hypertension in a Population-Based Sample of African Americans: The Jackson Heart Study.

The disproportionate rates of cardiovascular disease in African Americans may, in part, be due to suboptimal assessment of blood pressure (BP) with clinic BP measurements alone. To date, however, the prevalence of masked hypertension in African Americans has not been fully delineated. The purpose of this study was to evaluate masked hypertension prevalence in a large population-based sample of African Americans and examine its determinants and association with indices of target organ damage (TOD). Clinic and 24-hour ambulatory BP monitoring were conducted in 972 African Americans enrolled in the Jackson Heart Study. Common carotid artery intima-media thickness, left ventricular mass index, and the urinary albumin:creatinine excretion ratio were evaluated as indices of TOD. Masked hypertension prevalence was 25.9% in the overall sample and 34.4% in participants with normal clinic BP. All indices of TOD were significantly higher in masked hypertensives compared to sustained normotensives and were similar between masked hypertensives and sustained hypertensives. Male gender, smoking, diabetes, and antihypertensive medication use were independent determinants of masked hypertension in multivariate analyses. In this population-based cohort of African Americans, approximately one-third of participants with presumably normal clinic BP had masked hypertension when BP was assessed in their daily environment. Masked hypertension was accompanied by a greater degree of TOD in this cohort.

C-reactive protein and subclinical cardiovascular disease among African-Americans: (the Jackson Heart Study).

Systemic inflammation has been implicated as an early marker for subclinical cardiovascular disease; however, findings have been inconsistent in the African-American population. We examined the relation of C-reactive protein (CRP) to subclinical disease in African-American participants of the Jackson Heart Study first examination. Subclinical disease evaluated included aortic valve calcification (AVC), carotid intima-medial thickness (IMT) and peripheral arterial disease (PAD). We assessed the relation of CRP to subclinical disease, adjusting for age, BMI, sex, SBP and DBP, diabetes, total/high-density lipoprotein cholesterol, triglycerides, smoking, antihypertensive therapy, lipid-lowering therapy and hormone replacement therapy. In the study population approximately, 5.1% of participants had AVC and 6.7% had PAD. In the age-adjusted and sex-adjusted model, CRP was significantly related to AVC (P = 0.02) and carotid IMT (P = 0.02). However, in the multivariable-adjusted logistic regression analysis, CRP was significantly related to AVC (P = 0.02) and to PAD (P = 0.04) but not to carotid IMT (P = 0.18). We describe significant associations between CRP and AVC and PAD in a population-based cohort of African-Americans.

Gene-environment interaction between SCN5A-1103Y and hypokalemia influences QT interval prolongation in African Americans: The Jackson Heart Study

African-American ancestry, hypokalemia, and QT interval prolongation on the electrocardiogram are all risk factors for sudden cardiac death (SCD), but their interactions remain to be characterized. SCN5A-1103Y is a common missense variant, of African ancestry, of the cardiac sodium channel gene. SCN5A-1103Y is known to interact with QT-prolonging factors to promote ventricular arrhythmias in persons at high risk for SCD, but its clinical impact in the general African-American population has not been established. We genotyped SCN5A-S1103Y in 4,476 participants of the Jackson Heart Study, a population-based cohort of African Americans. We investigated the effect of SCN5A-1103Y, including interaction with hypokalemia, on QT interval prolongation, a widely-used indicator of prolonged myocardial repolarization and predisposition to SCD. We then evaluated the two sub-components of the QT interval: QRS duration and JT interval. The carrier frequency for SCN5A-1103Y was 15.4%. SCN5A-1103Y was associated with QT interval prolongation (2.7 milliseconds; P < .001) and potentiated the effect of hypokalemia on QT interval prolongation (14.6 milliseconds; P = .02). SCN5A-1103Y had opposing effects on the two sub-components of the QT interval, with shortening of QRS duration (-1.5 milliseconds; P = .001) and prolongation of the JT interval (3.4 milliseconds; P < .001). Hypokalemia was associated with diuretic use (78%; P < .001). SCN5A-1103Y potentiates the effect of hypokalemia on prolonging myocardial repolarization in the general African-American population. These findings have clinical implications for modification of QT prolonging factors, such as hypokalemia, in the 15% of African Americans who are carriers of SCN5A-1103Y.

Correlates of Isolated Nocturnal Hypertension and Target Organ Damage in a Population-Based Cohort of African Americans: The Jackson Heart Study

African Americans have higher rates of nocturnal hypertension and less nocturnal blood pressure (BP) dipping compared with whites. Although nocturnal hypertension is associated with increased cardiovascular morbidity and mortality, its clinical significance among those with normal daytime BP is unclear. This paper reports the prevalence and correlates of isolated nocturnal hypertension (INH) in a population-based cohort of African Americans enrolled in the Jackson Heart Study (JHS). The study sample included 425 untreated, normotensive and hypertensive JHS participants who underwent 24-hour ambulatory BP monitoring (ABPM), echocardiography, and 24-hour urine collection. Multiple logistic regression and 1-way analysis of variance models were used to test the hypothesis that those with INH have worse target organ damage reflected by greater left ventricular (LV) mass and proteinuria compared with normotensive participants. Based on 24-hour ABP profiles, 19.1% of participants had INH. In age and sex-adjusted models, participants with INH had greater LV mass compared with those who were normotensive (P = 0.02), as well as about 3 times the odds of LV hypertrophy and proteinuria (Ps < 0.10). However, multivariable adjustment reduced the magnitude and statistical significance of each of these differences. INH was associated with increased LV mass compared with normo tension in a population-based cohort of African Americans enrolled in the JHS. There were trends toward a greater likelihood of LV hyper trophy and proteinuria among participants with INH vs. those who were normotensive. The clinical significance of the noted target organ damage should be explored in this population.

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.

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 CRP's 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 CRP's 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 Predictive Value of Left Atrial Size for Incident Ischemic Stroke and All-Cause Mortality in African Americans

The association between left atrial (LA) size, ischemic stroke, and death has not been well established in African Americans despite their disproportionately higher rates of stroke and cardiovascular mortality compared to non-Hispanic whites. For the analysis, participants in the Jackson cohort of the Atherosclerosis Risk in Communities Study were followed from the date of the echocardiogram in cycle three to the date of the first ischemic stroke event (or death) or to December 31, 2004 if no ischemic stroke event (or death) was detected. There were 1886 participants in the study population (mean age 58.9 years, 65% women). Participants in the top quintile of LA diameter indexed to height (LA diameter/height; 2.57 to 3.55 cm/m) were more likely women, hypertensive, diabetic, and obese compared to those not in the top quintile. Over a median follow-up of 9.8 years for ischemic stroke and 9.9 years for all-cause mortality, there were 106 strokes and 242 deaths. In a multivariable model adjusting for traditional clinical risk factors, the top quintile of LA diameter/height was significantly related to ischemic stroke (HR 1.7; 95% CI: 1.1, 2.7) and all-cause mortality (HR 2.0; 95% CI: 1.5, 2.7). After further adjustment for left ventricular (LV) hypertrophy and low LV ejection fraction, the top quintile remained significantly related to all-cause mortality (HR 1.8; 95% CI: 1.3, 2.5). In this population-based cohort of African Americans, LA size was a predictor of all-cause mortality after adjusting for traditional cardiovascular risk factors, LV hypertrophy, and low LV ejection fraction.

Abstract 3616: Left Atrial Size Association with Incident Ischemic Stroke and All-Cause Mortality in African Americans: the Atherosclerosis Risks in Communities (ARIC) Study

Background: The association between left atrial (LA) size, ischemic stroke and mortality has been investigated in non-Hispanic whites but not in African Americans despite their disproportionately higher rates of stroke and cardiovascular mortality. Purpose: We examined the association of LA size assessed by echocardiogram with the incidence of ischemic stroke and all-cause mortality in a large population-based cohort of African Americans. Methods: Participants in the Jackson cohort of the ARIC study have been extensively evaluated including echocardiograms during the third examination (1993–1995) and have been followed for incident cardiovascular events including stroke. Results: The study population consisted of 1,887 participants of which 660 (35%) were men with a mean age of 58.9 ± 5.7 years. LA diameter by tertile was significantly related to hypertension, diabetes and body mass index (BMI) (p&lt;0.0001 for each). Over a median follow-up period of 8.8 years, there were 103 incident strokes (6.47 per 1,000 person-years) and 206 deaths (13.3 per 1,000 person-years). Adjusting for age, sex, hypertension, smoking, diabetes, total cholesterol:HDL ratio, and BMI, LA size was associated with stroke (HR per 10 mm increment of LA diameter 1.44; 95% CI: 0.99, 2.08, p = 0.05) and significantly associated with mortality (HR 1.38; 95% CI: 1.06,1.79 p &lt; 0.02). After further adjustment for prevalent CHD and congestive heart failure, only the association with mortality remained statistically significant (p &lt; 0.03). Conclusions: In this middle-aged population based cohort of African Americans, LA size was significantly associated with all-cause mortality independent of traditional cardiovascular risk factors.

THE EPIDEMIOLOGY, HERITABILITY, AND GENETIC LINKAGE OF C-REACTIVE PROTEIN IN THE JACKSON HEART STUDY.

Purpose There is limited information on CRP9s reference ranges, heritability, and relation to cardiovascular disease (CVD) risk factors and disease in African Americans. Methods The study consists of participants who underwent Exam 1 of the Jackson Heart Study (2001-2004). The distribution and correlates of CRP were analyzed for the entire study cohort. Heritability was estimated for the family cohort nested within the larger JHS (235 families, n = 1,364). The relations between CRP and traditional CVD risk factors were tested with multivariable stepwise regression analyses. Heritability was estimated using mixed-model regression analysis. QTL linkage analysis was performed using the multipoint variance components approach in SOLAR package. Results The study cohort consisted of 5,202 participants (55 ± 13 years, 64% female). The median CRP was 2.7 mg/L. In stepwise models traditional risk factors explained 23% of the variability of CRP, with BMI (partial R2 = 12.9%) explaining 57% of the variability of CRP due to traditional risk factors. The heritability for the age-, sex-, and BMI-adjusted CRP residual after winsorizing was 0.37, with a standard error (SE) of 0.06, and the heritability for the log transformed CRP residual was 0.45, with a SE of 0.06. The strongest evidence for linkage to CRP was observed on chromosome 3 (maximum LOD score of 2.92) near marker 295YC9P and chromosome 12 (maximum LOD score of 2.01) near marker D12S297. Conclusion In this large population-based cohort of African Americans, CRP concentrations were heritable and associated with several traditional cardiovascular risk factors, particularly with elevated BMI. Given the relationship between inflammation and CVD, further research into the genetic and environmental determinants of CRP is merited.

OBESITY, DIABETES, AND INSULIN RESISTANCE: RELATION TO ELEVATED C-REACTIVE PROTEIN LEVELS IN AFRICAN AMERICANS.

Purpose Elevated C-reactive protein (CRP) has been strongly related to obesity, diabetes (DM), and insulin resistance (IR) in predominantly white non-Hispanic cohorts. There is limited information on systemic inflammation in African Americans. Methods The study cohort consisted of 5,202 participants (55 ± 13 years, 64% female) who presented for Jackson Heart Study Exam 1 (2001-2004). The contribution of traditional risk factors to the variability of CRP was tested using a stepwise regression model. We evaluated the relation of obesity, DM and IR to CRP among participants using analysis of variance. Results In the stepwise regression, the amount of variability in CRP explained by clinical covariates was 23%. BMI explained 57% of the variability of CRP due to traditional risk factors. The mean CRP for participants was 1.4 mg/L for those nonobese without IR, 3.2 mg/L for those obese without IR, 2.2 mg/L for those nonobese with IR, 4.0 mg/L for those obese with IR, 1.9 mg/L for those nonobese with DM, and 4.1 mg/L for those obese with DM. CRP was significantly higher for obese participants compared with nonobese participants regardless of IR or DM status (p Conclusions In this large population-based cohort of African Americans, we found that among traditional risk factors, BMI contributed the greatest to the variability of CRP. DM and IR were also significantly related to CRP.