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BACKGROUND: We aimed to investigate the associations of glycemic markers (hemoglobin A(1C) [HbA(1C)], fasting plasma glucose [FPG] and glycemic status [normoglycemia, prediabetes and diabetes]) with incident heart failure (HF) and its subtypes, among Blacks. METHODS: We included 2,290 community-dwelling Blacks(64% women, mean age 58 years) without prevalent HF from the Jackson Heart Study who attended the second exam (2005–2008). The associations between glycemic markers and incident HF (and subtypes including HF with preserved ejection fraction [HFpEF] and reduced ejection fraction [HFrEF]) were evaluated using Cox proportional hazards regression models, adjusting for risk factors and coronary heart disease. RESULTS: There were 119 incident HF events (48 HFpEF, 58 HFrEF, and 13 unclassified HF events) over a median follow-up of 10.5 years. Higher levels of HbA(1C) (HR per SD increment, 1.30; 95% CI 1.12, 1.51) and FPG (HR per SD increment FPG: 1.32; 95% CI: 1.17, 1.48) were associated with a higher risk of incident HF. Compared to normal glycemia, diabetes status was associated with a higher risk of incident HF (HR: 1.24; 95%CI: 1.02, 2.05). HbA(1C) was significantly associated with higher risks of HFpEF (HR per SD increment: 1.41, 95% CI: 1.18, 1.69) and HFrEF (HR per SD increment: 1.32; 95% CI: 1.12, 1.56). FPG was significantly associated with higher risk of HFpEF (HR per SD increment: 1.35, 95% CI: 1.14, 1.62) but not HFrEF (HR per SD increment: 1.12; 95% CI: 0.53, 2.35). CONCLUSIONS: Among community-dwelling Blacks, higher levels of glycemic markers were associated with higher risk of HF subtypes. CLINICAL TRIALS. GOV IDENTIFIER: NCT00005485) of the Jackson Heart Study.

Background Little is known on the association of plasma adiponectin with blood pressure (BP) changes in African Americans (AAs). We evaluated the associations between plasma adiponectin and BP progression among AAs. Methods We analyzed data from 1,184 participants without hypertension at baseline (2000–2004) with ≥1 follow-up visits in the Jackson Heart Study. We used robust Poisson regression to generate risk ratios (RRs) for BP progression (an increase by ≥1 BP stage) and incident hypertension. Results Over a median of 7 years, 71% progressed to higher BP stage and 65% developed hypertension. We found evidence of interaction by sex (P-interaction = 0.088). Compared with those in the lowest quartile (Q1), male participants in the highest adiponectin quartile (Q4) had reduced risks of BP progression (RR 0.76 [95% confidence interval, CI, 0.60–0.96]) and incident hypertension (RR 0.74 [95% CI 0.56–0.97]). After accounting for body mass index, this relation persisted among obese men (RR for the highest [vs. lowest] adiponectin quartile: 0.59 [95% CI 0.36–0.97] for incident hypertension, and 0.69 [95% CI 0.45–1.06] for BP progression). Among women, adiponectin was not associated with BP outcomes (RR [95% CI] for Q4 vs. Q1: 1.03 [0.86–1.23] and 1.01 [0.83–1.23] for BP progression and incident hypertension, respectively). Our findings were consistent across both the American College of Cardiology (ACC)/American Heart Association (AHA) and Seventh Joint National Committee (JNC-7) BP categories. Conclusions In a large, community-based sample of AAs, higher adiponectin concentrations were associated with lower risks of BP progression and incident hypertension in men, but no significant association was observed in women.

OBJECTIVE There is a paucity of data on the relations of insulin resistance with incident blood pressure (BP) changes among Blacks. We investigated the associations of insulin resistance and metabolic syndrome (MetS) with BP progression in a community-based sample of African Americans. METHODS We analyzed 1064 participants without hypertension at baseline (2000-2004) who attended at least one follow-up visit in 2005-2008 or 2009-2013. Four insulin resistance indices [fasting insulin, insulin-to-glucose ratio (IGR), homeostasis model assessment of insulin resistance (HOMA-IR), and quantitative insulin sensitivity check index (QUICKI)] and MetS (excluding hypertension in the definition) were assessed at baseline. Robust Poisson regression was used to generate risk ratios (RRs) and 95% confidence intervals (CI) for BP progression and incident hypertension. RESULTS Over a median of 7 years, 69.6% progressed to a higher BP category and 62.7% developed hypertension. After multivariable adjustment, participants in the highest quartile of HOMA-IR had higher risks of BP progression [RR 1.25 (95% CI 1.09-1.43), Ptrend = 0.004] and hypertension [RR 1.35 (95% CI 1.16-1.58), Ptrend

Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease and is highly correlated with metabolic disease. NAFLD results from environmental exposures acting on a susceptible polygenic background. This study performed the largest multiethnic investigation of exonic variation associated with NAFLD and correlated metabolic traits and diseases. An exome array meta-analysis was carried out among eight multiethnic population-based cohorts (n = 16 492) with computed tomography (CT) measured hepatic steatosis. A fixed effects meta-analysis identified five exome-wide significant loci (P

Data on the relation of plasma leptin with blood pressure (BP) progression among Blacks are scant. We evaluated the association of plasma leptin levels with BP progression and incident hypertension among Blacks. We analyzed a total of 1190 Jackson Heart Study participants without hypertension at baseline (2000–2004) who attended ≥1 follow-up visit (2005–2008 or 2009–2013). Modified Poisson regression was used to generate multivariable-adjusted risk ratios (RRs) and 95% CIs for BP progression (an increase by ≥1 BP category) and incident hypertension (BP ≥130/80 or use of antihypertensive medication). Of the 1190 participants, 64.1% were women (n=763), mean age was 48 (SD: 12) years. Over a median of 7 years, 71.3% progressed to a higher BP category (n=848) and 64.6% developed hypertension (n=769). After adjusting for confounders, each SD increment in log-leptin was associated with higher risks of BP progression (RR, 1.10 [95% CI, 1.03–1.18], P =0.007) and incident hypertension (RR, 1.14 [95% CI, 1.05–1.23], P =0.002). Compared with those in the lowest leptin quartile, participants in the highest quartile had significantly higher risks of BP progression (RR, 1.27 [95% CI, 1.05–1.54], P trend =0.007) and incident hypertension (RR, 1.32 [95% CI, 1.07–1.64], Ptrend=0.010). These associations were consistent across multiple BP classifications. Our findings from a large cohort of Blacks support the notion that plasma leptin concentrations may help identify an at-risk population that could be targeted for hypertension prevention and management strategies in future studies.

Malaria and iron deficiency (ID) are common and interrelated public health problems in African children. Observational data suggest that interrupting malaria transmission reduces the prevalence of ID1. To test the hypothesis that malaria might cause ID, we used sickle cell trait (HbAS, rs334 ), a genetic variant that confers specific protection against malaria2, as an instrumental variable in Mendelian randomization analyses. HbAS was associated with a 30% reduction in ID among children living in malaria-endemic countries in Africa (n = 7,453), but not among individuals living in malaria-free areas (n = 3,818). Genetically predicted malaria risk was associated with an odds ratio of 2.65 for ID per unit increase in the log incidence rate of malaria. This suggests that an intervention that halves the risk of malaria episodes would reduce the prevalence of ID in African children by 49%. A genetic link suggests that interventions that halve the risk of malaria episodes could reduce the prevalence of iron deficiency in African children by nearly 50%.

Aims Almost half of African American (AA) men and women have cardiovascular disease (CVD). Detection of prevalent CVD in community settings would facilitate secondary prevention of CVD. We sought to develop a tool for automated CVD detection. Methods and results Participants from the Jackson Heart Study (JHS) with analysable electrocardiograms (ECGs) (n = 3679; age, 62 ± 12 years; 36% men) were included. Vectorcardiographic (VCG) metrics QRS, T, and spatial ventricular gradient vectors’ magnitude and direction, and traditional ECG metrics were measured on 12-lead ECG. Random forests, convolutional neural network (CNN), lasso, adaptive lasso, plugin lasso, elastic net, ridge, and logistic regression models were developed in 80% and validated in 20% samples. We compared models with demographic, clinical, and VCG input (43 predictors) and those after the addition of ECG metrics (695 predictors). Prevalent CVD was diagnosed in 411 out of 3679 participants (11.2%). Machine learning models detected CVD with the area under the receiver operator curve (ROC AUC) 0.69–0.74. There was no difference in CVD detection accuracy between models with VCG and VCG + ECG input. Models with VCG input were better calibrated than models with ECG input. Plugin-based lasso model consisting of only two predictors (age and peak QRS-T angle) detected CVD with AUC 0.687 [95% confidence interval (CI) 0.625–0.749], which was similar (P = 0.394) to the CNN (0.660; 95% CI 0.597–0.722) and better (P Conclusions Simple model (age and QRS-T angle) can be used for prevalent CVD detection in limited-resources community settings, which opens an avenue for secondary prevention of CVD in underserved communities.

Accruing evidence suggests an association between high-density lipoprotein cholesterol (HDL-C) and incident diabetes. However, there is a paucity of data on the link between HDL-C and diabetes, especially among African Americans (AAs). We aimed to assess the association of HDL-C and its fractions with incident type 2 diabetes among AAs.We included Jackson Heart Study participants who attended visit 1 (2001-2004), were free from diabetes and were not treated with lipid-modifying medications. Incident diabetes was assessed at two subsequent-yearly visits (2 and 3). We cross-sectionally assessed the association of HDL-C and insulin resistance (IR) using multivariable linear models. We prospectively assessed the association of HDL-C and its fractions with incident diabetes using multivariable Cox regression models.Among 2829 participants (mean age: 51.9 ± 12.4 years, 63.9% female), 487 participants (17%) developed new-onset diabetes, over a median follow-up of 8 years. In adjusted models, a higher HDL-C concentration was associated with a lower odds of IR (odds ratio [OR] per standard deviation [SD] increment: OR 0.56 [95% confidence interval, CI 0.50-0.63], p 0.001). In adjusted models, a higher HDL-C concentration was associated with a lower risk of diabetes (HR per SD increment: 0.78 [95% CI 0.71, 0.87], p 0.001; HR for highest vs. the lowest tertile of HDL-C was 0.56 [95% CI: 0.44, 0.71], p 0.001).In a sample of African-American adults not on any lipid-modifying therapy, high HDL-C concentrations were inversely associated with the risk of new-onset diabetes. These findings suggest a strong link between HDL-C metabolism and glucose regulation.

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program ( n = 63,302) and UK Biobank ( n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.

Brain natriuretic peptide (BNP) is elevated in decompensated systolic and diastolic heart failure. The plasma levels of adipokines, such as adiponectin and leptin, may provide evidence for mechanistic differences in BNP concentrations. African-American-specific associations are limited in the literature. The objective of this study was to evaluate the associations of adiponectin and leptin with BNP among African Americans. Methods Linear and logistic regressions were used to test the associations between adiponectin, leptin, and plasma BNP in 3738 participants of the Jackson Heart Study (JHS), a single-site prospective cohort study of African Americans in Jackson, Mississippi. Results A direct relationship of adiponectin was observed in multiple multivariate-adjusted linear models: in men (β = 0.41-0.47), and in women (β = 0.32-0.38). Those in the highest quartile of adiponectin expression were twice as likely to have elevated BNP levels after adjustment [odds ratio 2.66 (95% confidence interval, 1.66-4.34)]. An inverse relationship of leptin with BNP was observed (β = -0.15) but attenuated after adjustment for aldosterone, renin, and adiponectin. Conclusions Different linear associations of adiponectin and leptin with BNP were observed. Odds of elevated adiponectin were observed with elevated BNP in multivariate-adjusted models. This paradoxical relationship of adiponectin and plasma BNP is possibly explained through adiponectin resistance.

Rationale & Objective The relation of vascular stiffness, endothelial function, and kidney function is incompletely elucidated in African Americans. Our hypothesis was that increased vascular stiffness and endothelial dysfunction are associated with low estimated glomerular filtration rate (eGFR) and albuminuria in African Americans. Study Design Cross-sectional cohort analysis of data from the Jackson Heart Study. Settings & Patients 2,244 Jackson Heart Study participants (2012-2017 after Exam 3) who had undergone noninvasive hemodynamic assessment using arterial tonometry. Predictors Baseline carotid-femoral pulse wave velocity, pulsatile hemodynamics forward wave amplitude, and hyperemic brachial artery flow were measured. Reduced eGFR was defined as eGFR between 15 and 60 mL/min/1.73 m2. Outcomes Prevalent albuminuria, urinary albumin-creatinine ratio. Analytical Approach 2-sample t test for continuous variables and χ2 test for categorical variables in addition to logistic and linear regression models to assess the risk for chronic kidney disease with each proposed hemodynamic variable. Results Among 2,244 participants, mean age was 66 ± 11 years and 64% were women. Reduced eGFR was present in 233 (10.4%), and elevated urinary albumin-creatinine ratio, in 232 (10.4%). In multivariable-adjusted analyses, higher carotid-femoral pulse wave velocity was associated with the presence of reduced eGFR (OR, 1.37 [95% CI, 1.08-1.75] per SD; P = 0.01) and with prevalent albuminuria (OR, 1.66 [95% CI, 1.32-2.11]; P < 0.001). Higher forward wave amplitude was significantly associated with prevalent albuminuria (OR, 1.37 [95% CI, 1.14-1.65]; P = 0.001). Limitations Cross-sectional analyses cannot inform causality. Conclusions Higher arterial stiffness and pulsatility are associated with higher odds of reduced eGFR in African Americans. Future studies should focus on whether improving arterial stiffness contributes to kidney protection in African Americans., Graphical abstract

Despite pathophysiological links between endothelin (ET)-1 and hypertension in Black adults, there is no population-based data appraising the association of plasma ET-1 with longitudinal blood pressure (BP) changes in Blacks.We analyzed data from 1197 Jackson Heart Study participants without hypertension (mean age 47.8 years [SD: 12.0]; 64.2% women), with plasma ET-1 available at the baseline examination (2000-2004). Poisson regression with robust variance was used to generate risk ratios (RRs) and 95% confidence intervals (CIs) of BP progression (an increase by ≥1 BP category based on the 2017 American College of Cardiology/American Heart Association classification) and incident hypertension (BP ≥ 130/80 mm Hg or use of antihypertensive medication) at follow-up (2005-2008 or 2009-2013).Over a median follow-up of 7 years (range: 4-11), 71.2% (n = 854) progressed to a higher BP stage and 64.6% (n = 773) developed hypertension. After adjusting for possible confounders, each unit increment in baseline log (ET-1) was associated with higher risks of BP progression (RR 1.15 [95% CI 1.03-1.29], P = .016) and incident hypertension (RR 1.15 [95% CI 1.01-1.31], P = .032). Compared to those in the lowest ET-1 quartile, participants in the highest quartile had significantly higher risks of BP progression (RR 1.20 [95% CI 1.05-1.37], P = .007) and incident hypertension (RR 1.16 [95% CI 1.00-1.36], P = .052).In a large, community-based sample of African Americans, higher plasma ET-1 concentrations were associated with higher risks of BP progression and incident hypertension.

Publisher's version (útgefin grein)., Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles., This project was supported by a grant from the US National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (R01HL118305). This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. Tuomas O. Kilpeläinen was supported by the Danish Council for Independent Research (DFF–6110-00183) and the Novo Nordisk Foundation (NNF18CC0034900, NNF17OC0026848 and NNF15CC0018486). Diana van Heemst was supported by the European Commission funded project HUMAN (Health-2013-INNOVATION-1-602757). Susan Redline was supported in part by NIH R35HL135818 and HL11338. Study-specific acknowledgements can be found in the Supplementary Notes 2 and 4. The data on coronary artery disease have been contributed by the Myocardial Infarction Genetics and CARDIoGRAM investigators, and have been downloaded from www.CARDIOGRAMPLUSC4D.ORG.

BACKGROUND: 25-hydroxyvitamin D [25(OH)D] is lower in black compared with white Americans but is not consistently associated with outcomes in this group, possibly due to genetic and other biological differences. We examined the association of plasma 25(OH)D and renal outcomes in black Americans with a focus on effect modifiers. METHODS: We studied associations between baseline 25(OH)D with (i) annual rate of estimated glomerular filtration rate (eGFR) decline and (ii) incident chronic kidney disease (CKD) in the Jackson Heart Study, a prospective cohort of black Americans. Plasma 25(OH)D levels were corrected for monthly variation in sunlight exposure using the residual method. We used adjusted generalized linear models to evaluate outcomes and assessed potential effect modification by diabetes mellitus, vitamin D binding protein (DBP) genotype, obesity, dietary sodium intake, and use of renin-angiotensin-aldosterone system inhibitors. RESULTS: Among 5164 participants with 25(OH)D available, plasma 25(OH)D was 14.5 ± 6.5 ng/mL (mean ± SD), and eGFR was 94.1 ± 22.0 mL/min/1.73 m(2). Over a median of 8 years, eGFR decline was 1.3 ± 2.0 mL/min/1.73 m(2) per year in 3228 participants with complete data, and 220 out of 1803 eligible participants developed incident CKD. Overall, 25(OH)D was not associated with eGFR decline in fully adjusted models. However, higher 25(OH)D was associated with slower eGFR decline among those with diabetes: each 5 ng/mL higher 25(OH)D was associated with a 0.27 mL/min/1.73 m(2)/y slower eGFR decline (95% CI, 0.13 to 0.41; P < 0.001). Higher 25(OH)D was not associated with incident CKD overall, but it was associated with lower odds of incident CKD among participants with the GG or GT genotype at rs7041 in the gene encoding DBP [OR, 0.69 per 5 ng/mL higher 25(OH)D; 95% CI, 0.51 to 0.93; P-interaction = 0.005]. Other interactions were not significant. CONCLUSION: These findings support a potential benefit of higher 25(OH)D for kidney health in black Americans with diabetes or specific variants in DBP.

When testing genotype–phenotype associations using linear regression, departure of the trait distribution from normality can impact both Type I error rate control and statistical power, with worse ...

© The Author(s) 2019. A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-Alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2- degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10?6) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10?8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models. National Heart, Lung, and Blood Institute; American Heart Association Grant

Open in a separate window We hypothesized that identifying plasma glycoproteins that predict the development of heart failure following myocardial infarction (MI) could help to stratify subjects at risk. Plasma collected at visit 2 (2005–2008) from an MI subset of Jackson Heart Study participants underwent glycoproteomics and was grouped by the outcome: (1) heart failure hospitalization after visit 2 (n = 15) and (2) without hospitalization by 2012 (n = 45). Proteins were mapped for biological processes and functional pathways using Ingenuity Pathway Analysis and linked to clinical characteristics. A total of 198 glycopeptides corresponding to 88 proteins were identified (data available via ProteomeXchange with identifier PXD009870). Of these, 14 glycopeptides were significantly different between MI and MI + HF groups and corresponded to apolipoprotein (Apo) F, transthyretin, Apo C-IV, prostaglandin-D2 synthase, complement C9, and CD59 (p < 0.05 for all). All proteins were elevated in the MI + HF group, except CD59, which was lower. Four canonical pathways were upregulated in the MI + HF group (p < 0.05 for all): acute phase response, liver X receptor/retinoid X receptor, and macrophage reactive oxygen species generation. The coagulation pathway was significantly downregulated in the MI + HF group (p < 0.05). Even after adjustment for age and sex, Apo F was associated with the increased risk for heart failure (OR = 21.84; 95% CI 3.20–149.14). In conclusion, glycoproteomic profiling provided candidate early MI predictors of later progression to heart failure.

Leukocyte telomere length (LTL) is a biomarker of cellular aging. African Americans report more stress than other groups; however, the association of psychosocial stressors with biological aging among African Americans remains unclear. The current study evaluated the association of psychosocial factors (negative affect and stressors) with LTL in a large sample of African American men and women (n = 2,516) from the Jackson Heart Study. Using multivariable linear regression, we examined the sex-specific associations of psychosocial factors (cynical distrust, anger in and out, depressive symptoms, negative affect summary scores, global stress, weekly stress, major life events, and stress summary scores) with LTL. Model 1 adjusted for demographics and education. Model 2 adjusted for model 1, smoking, alcohol intake, physical activity, diabetes, hypertension, and high-sensitivity C-reactive protein. Among women, high (vs. low) cynical distrust was associated with shorter mean LTL in model 1 (b = -0.12; p = 0.039). Additionally, high (vs. low) anger out and expressed negative affect summary scores were associated with shorter LTL among women after full adjustment (b = -0.13; p = 0.011; b = -0.12, p = 0.031, respectively). High levels of cynical distrust, anger out, and negative affect summary scores may be risk factors for shorter LTL, particularly among African-American women.

Objective: Little is known about the moderation and mediation factors among the association between endothelin-1 (ET-1) level and type 2 diabetes progression in African Americans. We explored the role of high sensitivity C-reactive protein (hsCRP) as a moderator and homeostatic model assessment of insulin resistance (HOMA-IR) as a mediator for the association between ET-1 level and type 2 diabetes progression among African Americans enrolled in the Jackson Heart Study (JHS). Methods: We included 1,692 participants free of prediabetes and diabetes at baseline, who attended Exam 1 of the JHS in 2000-2004 and Exam 3 in 2009-2013, and with measured ET-1 level at Exam 1. Incident prediabetes and diabetes were ascertained at Exam 3. We used a sequential regression model procedure. Zou’s modified Poisson multivariable models were used to calculate risk ratios (RR) and 95% confidence intervals (CI) for prediabetes and diabetes. Effect modification was assessed in the multivariable adjusted model. Valeri and VanderWeele’s mediation analysis approach was utilized to evaluate mediation. Results: A higher log-transformed ET-1 level was detected when comparing non-diabetes versus prediabetes and diabetes participants (p-value for trend = 0.03). Compared to quartile 1 ( Conclusions: African Americans with higher ET-1 levels have a higher risk of prediabetes and diabetes. Additionally, the risk of diabetes is elevated among those African Americans with increased hsCRP levels. The mediation analysis result supports that ET-1 is involved in the stage of glucose metabolism imbalances leading to diabetes progression.

Background Black individuals have a higher burden of risk factors for heart failure (HF) and subclinical left ventricular remodeling. Methods and Results We evaluated 1871 Black participants in the Atherosclerosis Risk in Communities Study cohort who attended a routine examination (1993–1996, median age 58 years) when they underwent echocardiography. We estimated the prevalences of 4 HF stages: (1) Stage 0 : no risk factors; (2) Stage A : presence of HF risk factors (hypertension, diabetes mellitus, obesity, smoking, dyslipidemia, coronary artery disease without clinical myocardial infarction), no cardiac structural/functional abnormality; (3) Stage B : presence of prior myocardial infarction, systolic dysfunction, left ventricular hypertrophy, regional wall motion abnormality, or left ventricular enlargement; and (4) Stage C/D : prevalent HF. We assessed the incidence of clinical HF, atherosclerotic cardiovascular disease events, and all‐cause mortality on follow‐up according to HF stage. The prevalence of HF Stages 0, A, B, and C/D were 3.8%, 20.6%, 67.0%, and 8.6%, respectively, at baseline. On follow‐up (median 19.0 years), 309 participants developed overt HF, 390 incurred new‐onset cardiovascular disease events, and 651 individuals died. Incidence rates per 1000 person‐years for overt HF, cardiovascular disease events, and death, respectively, were Stage 0, 2.4, 0.8, and 7.6; Stage A, 7.4, 9.7, and 13.5; Stage B 13.6, 15.9, and 22.0. Stage B HF was associated with a 1.5‐ to 2‐fold increased adjusted risk of HF, cardiovascular disease events and death compared with Stages 0/A. Conclusions In our large community‐based sample of Black individuals, we observed a strikingly high prevalence of Stage B HF in middle age that was a marker of high cardiovascular morbidity and mortality.

Traditional Hardy–Weinberg equilibrium (HWE) tests (the χ2 test and the exact test) have long been used as a metric for evaluating genotype quality, as technical artifacts leading to incorrect genotype calls often can be identified as deviations from HWE. However, in data sets composed of individuals from diverse ancestries, HWE can be violated even without genotyping error, complicating the use of HWE testing to assess genotype data quality. In this manuscript, we present the Robust Unified Test for HWE (RUTH) to test for HWE while accounting for population structure and genotype uncertainty, and to evaluate the impact of population heterogeneity and genotype uncertainty on the standard HWE tests and alternative methods using simulated and real sequence data sets. Our results demonstrate that ignoring population structure or genotype uncertainty in HWE tests can inflate false-positive rates by many orders of magnitude. Our evaluations demonstrate different tradeoffs between false positives and statistical power across the methods, with RUTH consistently among the best across all evaluations. RUTH is implemented as a practical and scalable software tool to rapidly perform HWE tests across millions of markers and hundreds of thousands of individuals while supporting standard VCF/BCF formats. RUTH is publicly available at https://www.github.com/statgen/ruth.

Background Metabolic dyslipidemia (high triglyceride) and low high‐density lipoprotein cholesterol (HDL‐C) is highly prevalent in type 2 diabetes mellitus (T2DM). The extent to which diabetes mellitus–related abnormalities in the triglyceride–HDL‐C profile associates with cardiovascular disease (CVD) risk is incompletely understood. We evaluated the associations of triglyceride and HDL‐C status with CVD outcomes in individuals with T2DM. Methods and Results We analyzed data from 4199 overweight/obese adults with T2DM free of CVD with available data on triglyceride and HDL‐C at baseline (2001–2004) in the Look AHEAD (Action for Health in Diabetes) study. We used Cox proportional models to estimate hazard ratios (HRs) and 95% CIs of: (1) composite CVD outcome (myocardial infarction, stroke, hospitalization for angina, and/or death from cardiovascular causes); (2) coronary artery disease events; and (3) cerebrovascular accidents (stroke). Of the 4199 participants, 62% (n=2600) were women, with a mean age of 58 years (SD, 7), and 40% (n=1659) had metabolic dyslipidemia at baseline. Over a median follow‐up of 9.5 years (interquartile range, 8.7–10.3), 500 participants experienced the composite CVD outcome, 396 experienced coronary artery disease events, and 100 experienced stroke. Low HDL‐C was associated with higher hazards of the composite CVD outcome (HR, 1.36; 95% CI, 1.12–1.64 [ P =0.002]) and coronary artery disease events (HR, 1.46; 95% CI, 1.18–1.81 [ P =0.001]) but not stroke (HR, 1.38; 95% CI, 0.90–2.11 [ P =0.140]). Compared with patients with normal triglyceride and normal HDL, participants with metabolic dyslipidemia had higher risks of the composite CVD outcome (HR, 1.30; 95% CI, 1.03–1.63 [ P =0.025]) and coronary artery disease events (HR, 1.48; 95% CI, 1.14–1.93 [ P =0.003]) but not stroke (HR, 1.23; 95% CI, 0.74–2.05 [ P =0.420]). Conclusions In a large sample of overweight/obese individuals with T2DM, metabolic dyslipidemia was associated with higher risks of CVD outcomes. Our findings highlight the necessity to account for metabolic dyslipidemia in CVD risk stratification among patients with T2DM. Registration URL: https://www.lookaheadtrial.org ; Unique identifier: NCT00017953 .

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in Trans-Omics for Precision Medicine (TOPMed) program (N=63,302) and UK Biobank (N=48,658). Bidirectional Mendelian randomization studies were consistent with LTL lengthening increasing propensity to develop CHIP, but CHIP then in turn hastening LTL shortening. We also demonstrated evidence of modest mediation between CHIP and CAD by LTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.

ObjectivesWe hypothesised that (1) the prevalent cardiovascular disease (CVD) is associated with global electrical heterogeneity (GEH) after adjustment for demographic, anthropometric, socioeconomic and traditional cardiovascular risk factors, (2) there are sex differences in GEH and (3) sex modifies an association of prevalent CVD with GEH.DesignCross-sectional, cohort study.SettingProspective African-American The Jackson Heart Study (JHS) with a nested family cohort in 2000–2004 enrolled residents of the Jackson, Mississippi metropolitan area.ParticipantsParticipants from the JHS with analysable ECGs recorded in 2009–2013 (n=3679; 62±12 y; 36% men; 863 family units). QRS, T and spatial ventricular gradient (SVG) vectors’ magnitude and direction, spatial QRS-T angle and sum absolute QRST integral (SAI QRST) were measured.OutcomePrevalent CVD was defined as the history of (1) coronary heart disease defined as diagnosed/silent myocardial infarction, or (2) revascularisation procedure defined as prior coronary/peripheral arterial revascularisation, or (3) carotid angioplasty/carotid endarterectomy, or (4) stroke.ResultsIn adjusted mixed linear models, women had a smaller spatial QRS-T angle (−12.2 (95% CI −19.4 to -5.1)°; p=0.001) and SAI QRST (−29.8 (−39.3 to −20.3) mV*ms; pConclusionsThere are sex differences in the electrical signature of CVD in African-American men and women. There is a significant effect of unmeasured genetic and environmental factors on cardiac repolarisation.

In response to the growing trends of cardiovascular disease (CVD) morbidity and mortality among African Americans (AAs) nationwide and in Mississippi, a widening gap in health disparities and the recommendation for a study similar to the Framingham Heart Study in a minority population, the Jackson Heart Study (JHS) was funded in 1999 by the National Institutes of Health, National Heart, Lung, and Blood Institute. Prior to the JHS, no study had comprehensively evaluated the combined contributions of traditional risk factors, novel risk factors including psychosocial determinants of health and noncardiac target-organ-disease to the risk of CVD, cardiac remodeling, and congestive heart failure in an AA community-based group. JHS investigators and collaborators learned lessons about hypertension, obesity, diabetes mellitus (DM) and metabolic syndrome hypercholesterolemia, cigarette smoking, physical inactivity, and diet unique to the AA population. JHS investigators and collaborators learned that hypertension is associated with a larger proportion of CVDs than other traditional risk factors including DM. Genetic data from the JHS cohort contribute notably to lessons learned about admixture mapping, genome-wide association studies, exome analysis, and candidate gene analysis. Beyond the scope of this chapter which focuses on research discovery, the JHS should be understood to be a large set of coordinated programs and centers across academic and governmental entities. This overall effort, while driven by the epidemiological questions of health disparities, includes active community engagement and highly successful undergraduate and graduate training programs. Lessons learned over a 20-year period are guiding the JHS into the next decade, which will include interventional research and multiple technology-assisted approaches.

Aim To evaluate the association between plasma biomarkers including leptin, adiponectin, adiponectin-to-leptin ratio and high-sensitivity C-reactive protein (hsCRP) with risk of glycaemic progression and incident dysglycaemia (pre-diabetes or diabetes) in a community-based sample of African American (AAs). Methods We analysed data from 3223 participants without type 2 diabetes at baseline (2000-2004) who attended ≥1 follow-up visit. Poisson regression was used to generate risk ratios (RRs) for glycaemic progression and incident dysglycaemia. Results Over a median of 7 years, 46.4% developed glycaemic progression (n=1495). After adjusting for demographic and lifestyle variables, the RRs (95% CI) for glycaemic progression comparing highest (Q4) to lowest (Q1) quartiles were 1.30 (1.10-1.54), 0.74 (0.65-0.84), 0.70 (0.62-0.80) and 1.22 (1.07-1.38) for leptin, adiponectin, adiponectin-leptin ratio and hsCRP, respectively. Upon additional adjustment for BMI, the corresponding RRs (95% CIs) were 1.15 (0.94-1.42), 0.76 (0.67-0.86), 0.72 (0.62-0.84) and 1.14 (0.99-1.31) respectively. Among participants with normal glycaemia, the RRs (95% CIs) for incident pre-diabetes in Q4 vs Q1 were 1.37 (1.13-1.67), 0.73 (0.63-0.85), 0.70 (0.59-0.82) and 1.28 (1.10-1.48) for leptin, adiponectin, adiponectin-leptin ratio and hsCRP, respectively; equivalent RRs for incident diabetes were 5.15 (2.63-10.10), 0.36 (0.20-0.68), 0.21 (0.12-0.38) and 3.04 (1.70-5.44), respectively. Conclusions In this large community-based cohort of AAs, our results suggest that high plasma leptin and hsCRP, as well as low adiponectin and adiponectin-to-leptin ratio, are associated with higher risks of glycaemic progression. The findings point to the potential utility of these biomarkers in predicting and preventing glycaemic progression in this high-risk population.

Pharmaceutical drugs targeting dyslipidemia and cardiovascular disease (CVD) may increase the risk of fatty liver disease and other metabolic disorders. To identify potential novel CVD drug targets without these adverse effects, we perform genome-wide analyses of participants in the HUNT Study in Norway (n = 69,479) to search for protein-altering variants with beneficial impact on quantitative blood traits related to cardiovascular disease, but without detrimental impact on liver function. We identify 76 (11 previously unreported) presumed causal protein-altering variants associated with one or more CVD- or liver-related blood traits. Nine of the variants are predicted to result in loss-of-function of the protein. This includes ZNF529:p.K405X, which is associated with decreased low-density-lipoprotein (LDL) cholesterol (P = 1.3 × 10−8) without being associated with liver enzymes or non-fasting blood glucose. Silencing of ZNF529 in human hepatoma cells results in upregulation of LDL receptor and increased LDL uptake in the cells. This suggests that inhibition of ZNF529 or its gene product should be prioritized as a novel candidate drug target for treating dyslipidemia and associated CVD., Drugs targeting cardiovascular disease (CVD) can have negative consequences for liver function. Here, the authors combine genome wide analyses on 69,479 individuals to identify loss-of-function variants with beneficial effects on CVD-related traits without negative impacts on liver function.

Introduction: Cigarette smoking is associated with peripheral artery disease (PAD) in African Americans (AA), but the association between cigarette constituents and PAD remain inadequately studied. We evaluated the effect of volatile organic compounds (VOC) acrolein and crotonaldehyde on ankle-brachial index (ABI) as well as related biomarkers in AA participants of the Jackson Heart Study. Methods: Urinary VOC concentrations were measured in a subset of participants at baseline including 345 self-reported current smokers and 718 never smokers. Multivariable linear regression assessed the association between ABI and VOC concentrations after adjustment for acute (cotinine) and chronic (pack-years) smoking measures in models 1 and 2, respectively. The degree of association was assessed after adjusting for possible mediation (Baron & Kenny procedure) by C-reactive protein (CRP), fibrinogen, and homocysteine (HCY) concentrations. VOC concentrations were natural log transformed for normal distribution and all models adjusted for relevant covariates. Results: The mean age of included participants was 52 years and 49% women. Individuals who smoked were more likely to be men, less educated, have prevalent cardiovascular disease, and lower mean ABI. In model 1, ABI was inversely associated with urinary acrolein and crotonaldehyde concentrations. Model 2 retained the inverse ABI association for both VOC. Crotonaldehyde was directly associated with CRP and HCY in models 1 and 2. In model 1, acrolein was associated with HCY (Table). Biomarker mediation of the VOC-ABI relationship was insignificant. Conclusions: Acrolein and crotonaldehyde concentrations are associated with lower ABI and higher measures of inflammation and thrombosis in a community-based sample of AA. These findings suggest reduction in VOC exposure may reduce the risk of PAD in AA who smoke cigarettes.