Jackson Heart Study

articles nature publishing group epidemiology IntroductIon Excessive adiposity is a major cause of hypertension, dyslipidemia, and type 2 diabetes mellitus (T2DM) (1). As these clinical risk factors are known to be the primary precursors of cardiovascular disease (CVD), they have become the focus of most primary CVD prevention efforts. BMI is a useful indicator of overall adiposity, and recent National Health and Nutrition Examination Study (NHANES) data demonstrate that two-thirds of the US population is either overweight or obese (2), with the prevalence of obesity among African Americans exceeding that of whites of European ancestry. Although CVD death rates are higher in African Americans, than in whites, the reasons for this disparity are poorly understood (3). Prior studies have suggested that for a given BMI category, rates of CVD death among African Americans are lower compared to whites (4-13). However, the association of obesity with CVD risk factors in African Americans vs. whites has not been studied thoroughly.

White blood cell count (WBC) is an important clinical marker that varies among different ethnic groups. African Americans are known to have a lower WBC than European Americans. We surveyed the entire genome for loci underlying this difference in WBC by using admixture mapping. We analyzed data from African American participants in the Health, Aging, and Body Composition Study and the Jackson Heart Study. Participants of both studies were genotyped across R 1322 single nucleotide polymorphisms that were preselected to be informative for African versus European ancestry and span the entire genome. We used these markers to estimate genetic ancestry in each chromosomal region and then tested the association between WBC and genetic ancestry at each locus. We found a locus on chromosome 1q strongly associated with WBC (p < 10 À12 ). The strongest association was with a marker known to affect the expression of the Duffy blood group antigen. Participants who had both copies of the common West African allele had a mean WBC of 4.9 (SD 1.3); participants who had both common European alleles had a mean WBC of 7.1 (SD 1.3). This variant explained~20% of population variation in WBC. We used admixture mapping, a novel method for conducting genetic-association studies, to find a region that was significantly associated with WBC on chromosome 1q. Additional studies are needed to determine the biological mechanism for this effect and its clinical implications.

Background: African Americans have an increased incidence and worse prognosis with chronic kidney disease (CKD -estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m 2 ) than their counterparts of Europeandescent. 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. Methods: We 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 communitybased Jackson Heart Study's 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). Results: Participants (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).

Lipoprotein(a) (Lp(a)) is an important causal cardiovascular risk factor, with serum Lp(a) levels predicting atherosclerotic heart disease and genetic determinants of Lp(a) levels showing association with myocardial infarction. Lp(a) levels vary widely between populations, with African-derived populations having nearly 2-fold higher Lp(a) levels than European Americans. We investigated the genetic basis of this difference in 4464 African Americans from the Jackson Heart Study (JHS) using a panel of up to 1447 ancestry informative markers, allowing us to accurately estimate the African ancestry proportion of each individual at each position in the genome. In an unbiased genome-wide admixture scan for frequencydifferentiated genetic determinants of Lp(a) level, we found a convincing peak (LOD = 13.6) at 6q25.3, which spans the LPA locus. Dense fine-mapping of the LPA locus identified a number of strongly associated, common biallelic SNPs, a subset of which can account for up to 7% of the variation in Lp(a) level, as well as .70% of the African-European population differences in Lp(a) level. We replicated the association of the most strongly associated SNP, rs9457951 (p = 6610 222 , 27% change in Lp(a) per allele, ,5% of Lp(a) variance explained in JHS), in 1,726 African Americans from the Dallas Heart Study and found an even stronger association after adjustment for the kringle(IV) repeat copy number. Despite the strong association with Lp(a) levels, we find no association of any LPA SNP with incident coronary heart disease in 3,225 African Americans from the Atherosclerosis Risk in Communities Study.

Chronic kidney disease (CKD) leads to end-stage renal disease and is a growing epidemic throughout the world. In the United States, African Americans have an incidence of end-stage renal disease 4 times that of whites.Cross-sectional to examine the prevalence and awareness of CKD in African Americans.Observational cohort in the Jackson Heart Study (JHS).CKD was defined as an estimated glomerular filtration rate less than 60 mL/min/1.73 m2, the presence of albuminuria, or dialysis therapy.Data from the JHS were analyzed. Medical history, including disease awareness and drug therapy, anthropometric measurements, and serum and urine samples, were obtained from JHS participants at the baseline visit. Associations between CKD prevalence and awareness and selected demographic, socioeconomic, health care access, and disease status parameters were assessed by using logistic regression models.The prevalence of CKD in the JHS was 20%; CKD awareness was only 15.8%. Older participants had a greater prevalence, but also were more aware of CKD. Hypertension, diabetes, cardiovascular disease, hypercholesterolemia, hypertriglyceridemia, increasing age and waist circumference, and being single or less physically active were associated with CKD. Only advancing CKD stage was associated with awareness.Cross-sectional assessment, single urine measurement.The JHS has a high prevalence and low awareness of CKD, especially in those with less severe disease status. This emphasizes the need for earlier diagnosis and increased education of health care providers and the general population.

Socioeconomic status (SES) is recognized as a key social environmental factor because it has implications for access to resources that help individuals care for themselves and others. Few studies have examined the association of SES with chronic kidney disease (CKD) in high-risk populations.Single-site longitudinal population-based cohort.Data for this study were drawn from the baseline examination of the Jackson Heart Study. The analytic cohort consisted of 3,430 African American men and women living in the tricounty region of the Jackson, MS, metropolitan area with complete data to determine CKD status.High SES (defined as having a family income at least 3.5 times the poverty level or having at least 1 undergraduate degree).CKD (defined as the presence of albuminuria or decreased estimated glomerular filtration rate [<60 mL/min/1.73 m2]). Associations were explored using bivariable analyses and multivariable logistic regression analyses adjusting for CKD and cardiovascular disease risk factors, as well as demographic factors.The prevalence of CKD in the Jackson Heart Study was 20% (865 of 3,430 participants). Proportions of the Jackson Heart Study cohort with albuminuria and decreased estimated glomerular filtration rate were 12.5% (429 of 3,430 participants) and 10.1% (347 of 3,430 participants), respectively. High SES was associated inversely with CKD. The odds of having CKD were 41% lower for affluent participants than their less affluent counterparts. There were no statistically significant interactions between sex and education or income, although subgroup analysis showed that high income was associated with CKD in men (OR, 0.47; 95% CI, 0.23-0.97), but not women (OR, 0.64; 95% CI, 0.40-1.03).Models were estimated using cross-sectional data.CKD is associated with SES. Additional research is needed to elucidate the impact of wealth and social contexts in which individuals are embedded and the mediating effects of sociocultural factors.

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 = 2.7610 26 ) 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.

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 = 2.7610 26 ) 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.

Despite the high prevalence of cardiovascular disease documented among the African-American population, there has been little emphasis on the role of dyslipidemia as a prominent risk factor in this large subpopulation. Questions of medication efficacy also have been raised. Together, these factors may have affected awareness, diagnosis, and treatment rates. METHODS AND RESULTS: Dyslipidemia was defined as the presence of either hypercholesterolemia or hypertriglyceridemia using National Cholesterol Education Program III criteria and the fasting lipid measurements, self-reported treatment history, and medication survey available from 5302 Jackson Heart Study participants. Dyslipidemia was more common in men (compared with women) aged less than 50 years and increased with age in both genders. Hypercholesterolemia prevalence rates approached 50% in women aged more than 65 years. The lifestyle-related attributes found to be related to prevalence were being overweight and less physically active, and all disease status variables exhibited significant (P Ͻ .05) associations. Awareness of hypercholesterolemia is approximately 55% or more in both men and women aged more than 35 years. Treatment rates lag far behind awareness, particularly in younger adult men, and less than 50% of women and men aged less than 65 years were treated for hypercholesterolemia. CONCLUSION: Higher rates of identification and effective treatment of dyslipidemia are clearly needed in this, and probably other African-American communities. Despite the less than optimal treatment, the identification and importance of the known cardiovascular disease states and risk factors in these analyses suggest the adoption of National Cholesterol Education Program III "high-risk strategy" algorithms in treatment recommendations and decisions by providers is occurring.

Background: Electrocardiographic QT interval prolongation is a risk factor for sudden cardiac death (SCD) and drug-induced arrhythmia. The clinical correlates and heritability of QT interval duration in African Americans have not been well studied despite their higher risk for SCD compared to non-Hispanic whites. We sought to investigate potential correlates of the QT interval and estimate its heritability in the Jackson Heart Study (JHS).

White blood cell count (WBC) is an important clinical marker that varies among different ethnic groups. African Americans are known to have a lower WBC than European Americans. We surveyed the entire genome for loci underlying this difference in WBC by using admixture mapping. We analyzed data from African American participants in the Health, Aging, and Body Composition Study and the Jackson Heart Study. Participants of both studies were genotyped across R 1322 single nucleotide polymorphisms that were preselected to be informative for African versus European ancestry and span the entire genome. We used these markers to estimate genetic ancestry in each chromosomal region and then tested the association between WBC and genetic ancestry at each locus. We found a locus on chromosome 1q strongly associated with WBC (p < 10 À12 ). The strongest association was with a marker known to affect the expression of the Duffy blood group antigen. Participants who had both copies of the common West African allele had a mean WBC of 4.9 (SD 1.3); participants who had both common European alleles had a mean WBC of 7.1 (SD 1.3). This variant explained~20% of population variation in WBC. We used admixture mapping, a novel method for conducting genetic-association studies, to find a region that was significantly associated with WBC on chromosome 1q. Additional studies are needed to determine the biological mechanism for this effect and its clinical implications.

The risk of type 2 diabetes is approximately 2-fold higher in African Americans than in European Americans even after adjusting for known environmental risk factors, including socioeconomic status (SES), suggesting that genetic factors may explain some of this population difference in disease risk. However, relatively few genetic studies have examined this hypothesis in a large sample of African Americans with and without diabetes. Therefore, we performed an admixture analysis using 2,189 ancestry-informative markers in 7,021 African Americans (2,373 with type 2 diabetes and 4,648 without) from the Atherosclerosis Risk in Communities Study, the Jackson Heart Study, and the Multiethnic Cohort to 1) determine the association of type 2 diabetes and its related quantitative traits with African ancestry controlling for measures of SES and 2) identify genetic loci for type 2 diabetes through a genome-wide admixture mapping scan. The median percentage of African ancestry of diabetic participants was slightly greater than that of non-diabetic participants (study-adjusted difference = 1.6%, P,0.001). The odds ratio for diabetes comparing participants in the highest vs. lowest tertile of African ancestry was 1.33 (95% confidence interval 1.13-1.55), after adjustment for age, sex, study, body mass index (BMI), and SES. Admixture scans identified two potential loci for diabetes at 12p13.31 (LOD = 4.0) and 13q14.3 (Z score = 4.5, P = 6.6610 26 ). In conclusion, genetic ancestry has a significant association with type 2 diabetes above and beyond its association with nongenetic risk factors for type 2 diabetes in African Americans, but no single gene with a major effect is sufficient to explain a large portion of the observed population difference in risk of diabetes. There undoubtedly is a complex interplay among specific genetic loci and non-genetic factors, which may both be associated with overall admixture, leading to the observed ethnic differences in diabetes risk.

African Americans have historically had high high-density lipoprotein cholesterol (HDL-C) compared with other races and ethnicities.We sought to characterize whether there is a cross-sectional association between age and HDL-C in a contemporary community-based study of African Americans.Cross-sectional data were modeled by logistic regression for predictors of HDL-C among African Americans, ages 35–74, participating in the baseline examination of a community-based study of cardiovascular disease in Jackson, Mississippi, during 2000–2004. After excluding persons taking lipid-lowering medications, hormone replacement therapy, oral contraceptives, or thyroid replacement, the analytical data set comprised 2420 persons (1370 women, 1050 men).HDL-C had a significant positive association with age after controlling for serum triglycerides, sex, waist circumference, percent dietary calories from carbohydrates, alcohol use, and leisure physical activity. Sex was a significant effect modifier of this relationship, whereby the increase in HDL-C with age was steeper for women than for men.Cross-sectional analysis found a positive association of HDL-C with age while controlling for triglycerides. Careful evaluation of longitudinal data will be needed to confirm whether this is a true effect of aging, or a cohort or survivor effect.