Rare coding variants in RCN3 are associated with blood pressure.

BACKGROUND: While large genome-wide association studies have identified nearly one thousand loci associated with variation in blood pressure, rare variant identification is still a challenge. In family-based cohorts, genome-wide linkage scans have been successful in identifying rare genetic variants for blood pressure. This study aims to identify low frequency and rare genetic variants within previously reported linkage regions on chromosomes 1 and 19 in African American families from the Trans-Omics for Precision Medicine (TOPMed) program. Genetic association analyses weighted by linkage evidence were completed with whole genome sequencing data within and across TOPMed ancestral groups consisting of 60,388 individuals of European, African, East Asian, Hispanic, and Samoan ancestries. RESULTS: Associations of low frequency and rare variants in RCN3 and multiple other genes were observed for blood pressure traits in TOPMed samples. The association of low frequency and rare coding variants in RCN3 was further replicated in UK Biobank samples (N = 403,522), and reached genome-wide significance for diastolic blood pressure (p = 2.01 × 10- 7). CONCLUSIONS: Low frequency and rare variants in RCN3 contributes blood pressure variation. This study demonstrates that focusing association analyses in linkage regions greatly reduces multiple-testing burden and improves power to identify novel rare variants associated with blood pressure traits.

Dysglycemia and incident heart failure among blacks: The jackson heart study.

BACKGROUND: We aimed to investigate the associations of glycemic markers (hemoglobin A1C [HbA1C], 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 HbA1C (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). HbA1C 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.

Cost-effectiveness of Contemporary Statin Use Guidelines With or Without Coronary Artery Calcium Assessment in African American Individuals.

Importance: Clinical and economic consequences of statin treatment guidelines supplemented by targeted coronary artery calcium (CAC) assessment have not been evaluated in African American individuals, who are at increased risk for atherosclerotic cardiovascular disease and less likely than non-African American individuals to receive statin therapy. Objective: To evaluate the cost-effectiveness of the 2013 American College of Cardiology/American Heart Association (ACC/AHA) guideline without a recommendation for CAC assessment vs the 2018 ACC/AHA guideline recommendation for use of a non-0 CAC score measured on one occasion to target generic-formulation, moderate-intensity statin treatment in African American individuals at risk for atherosclerotic cardiovascular disease. Design, Setting, and Participants: A microsimulation model was designed to estimate life expectancy, quality of life, costs, and health outcomes over a lifetime horizon. African American-specific data from 472 participants in the Jackson Heart Study (JHS) at intermediate risk for atherosclerotic cardiovascular disease and other US population-specific data on individuals from published sources were used. Data analysis was conducted from November 11, 2018, to November 1, 2019. Main Outcomes and Measures: Lifetime costs and quality-adjusted life-years (QALYs), discounted at 3% annually. Results: In a model-based economic evaluation informed in part by follow-up data, the analysis was focused on 472 individuals in the JHS at intermediate risk for atherosclerotic cardiovascular disease; mean (SD) age was 63 (6.7) years. The sample included 243 women (51.5%) and 229 men (48.5%). Of these, 178 of 304 participants (58.6%) who underwent CAC assessment had a non-0 CAC score. In the base-case scenario, implementation of 2013 ACC/AHA guidelines without CAC assessment provided a greater quality-adjusted life expectancy (0.0027 QALY) at a higher cost ($428.97) compared with the 2018 ACC/AHA guideline strategy with CAC assessment, yielding an incremental cost-effectiveness ratio of $158 325/QALY, which is considered to represent low-value care by the ACC/AHA definition. The 2018 ACC/AHA guideline strategy with CAC assessment provided greater quality-adjusted life expectancy at a lower cost compared with the 2013 ACC/AHA guidelines without CAC assessment when there was a strong patient preference to avoid use of daily medication therapy. In probability sensitivity analyses, the 2018 ACC/AHA guideline strategy with CAC assessment was cost-effective compared with the 2013 ACC/AHA guidelines without CAC assessment in 76% of simulations at a willingness-to-pay value of $100 000/QALY when there was a preference to lose 2 weeks of perfect health to avoid 1 decade of daily therapy. Conclusions and Relevance: A CAC assessment-guided strategy for statin therapy appears to be cost-effective compared with initiating statin therapy in all African American individuals at intermediate risk for atherosclerotic cardiovascular disease and may provide greater quality-adjusted life expectancy at a lower cost than a non-CAC assessment-guided strategy when there is a strong patient preference to avoid the need for daily medication. Coronary artery calcium testing may play a role in shared decision-making regarding statin use.

Ambulatory Blood Pressure Phenotypes in Adults Taking Antihypertensive Medication with and without CKD.

BACKGROUND AND OBJECTIVES: Recent guidelines recommend out-of-clinic BP measurements. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We compared the prevalence of BP phenotypes between 561 black patients, with and without CKD, taking antihypertensive medication who underwent ambulatory BP monitoring at baseline (between 2000 and 2004) in the Jackson Heart Study. CKD was defined as an albumin-to-creatinine ratio ≥30 mg/g or eGFR <60 ml/min per 1.73 m2. Sustained controlled BP was defined by BP at goal both inside and outside of the clinic and sustained uncontrolled BP as BP above goal both inside and outside of the clinic. Masked uncontrolled hypertension was defined by controlled clinic-measured BP with uncontrolled out-of-clinic BP. RESULTS: CKD was associated with a higher multivariable-adjusted prevalence ratio for uncontrolled versus controlled clinic BP (prevalence ratio, 1.44; 95% CI, 1.02 to 2.02) and sustained uncontrolled BP versus sustained controlled BP (prevalence ratio, 1.66; 95% CI, 1.16 to 2.36). There were no statistically significant differences in the prevalence of uncontrolled daytime or nighttime BP, nondipping BP, white-coat effect, and masked uncontrolled hypertension between participants with and without CKD after multivariable adjustment. After multivariable adjustment, reduced eGFR was associated with masked uncontrolled hypertension versus sustained controlled BP (prevalence ratio, 1.42; 95% CI, 1.00 to 2.00), whereas albuminuria was associated with uncontrolled clinic BP (prevalence ratio, 1.76; 95% CI, 1.20 to 2.60) and sustained uncontrolled BP versus sustained controlled BP (prevalence ratio, 2.02; 95% CI, 1.36 to 2.99). CONCLUSIONS: The prevalence of BP phenotypes defined using ambulatory BP monitoring is high among adults with CKD taking antihypertensive medication.

Leveraging linkage evidence to identify low-frequency and rare variants on 16p13 associated with blood pressure using TOPMed whole genome sequencing data.

In this study, we investigated low-frequency and rare variants associated with blood pressure (BP) by focusing on a linkage region on chromosome 16p13. We used whole genome sequencing (WGS) data obtained through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program on 395 Cleveland Family Study (CFS) European Americans (CFS-EA). By analyzing functional coding variants and non-coding rare variants with CADD score > 10 residing within the chromosomal region in families with linkage evidence, we observed 25 genes with nominal statistical evidence (burden or SKAT p < 0.05). One of the genes is RBFOX1, an evolutionarily conserved RNA-binding protein that regulates tissue-specific alternative splicing that we previously reported to be associated with BP using exome array data in CFS. After follow-up analysis of the 25 genes in ten independent TOPMed studies with individuals of European, African, and East Asian ancestry, and Hispanics (N = 29,988), we identified variants in SLX4 (p = 2.19 × 10-4) to be significantly associated with BP traits when accounting for multiple testing. We also replicated the associations previously reported for RBFOX1 (p = 0.007). Follow-up analysis with GTEx eQTL data shows SLX4 variants are associated with gene expression in coronary artery, multiple brain tissues, and right atrial appendage of the heart. Our study demonstrates that linkage analysis of family data can provide an efficient approach for detecting rare variants associated with complex traits in WGS data.

Modifiers of Plasma 25-Hydroxyvitamin D and Chronic Kidney Disease Outcomes in Black Americans: The Jackson Heart Study.

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 m2. Over a median of 8 years, eGFR decline was 1.3 ± 2.0 mL/min/1.73 m2 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 m2/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.

Dietary Phosphorus and Ambulatory Blood Pressure in African Americans: The Jackson Heart Study.

BACKGROUND: Higher dietary phosphorus is associated with left ventricular hypertrophy and mortality, which are blood pressure (BP)-related outcomes. For this reason, we hypothesized that dietary phosphorus may be associated with adverse clinic and ambulatory BP patterns. METHODS: Our study included 973 African American adults enrolled in the Jackson Heart Study (2000-2004) with 24-hour ambulatory BP monitoring (ABPM) data at baseline. We quantified dietary phosphorus from a validated Food Frequency Questionnaire as follows: (i) absolute daily intake, (ii) ratio of phosphorus-to-protein intake, (iii) phosphorus density, and (iv) energy-adjusted phosphorus intake. Using multivariable linear regression, we determined associations between dietary phosphorus intake and systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure in clinic and over daytime, nighttime, and 24-hour periods from ABPM. Extent of nocturnal BP dipping was also assessed. Using logistic regression, we modeled relationships between dietary phosphorus intake and clinically relevant qualitative BP phenotypes, such as masked, sustained, or white-coat hypertension and normotension. RESULTS: There were no statistically significant associations between phosphorus intake and SBP or pulse pressure in adjusted models. Most metrics of higher phosphorus intake were associated with lower daytime, nighttime, and clinic DBP. Higher phosphorus intake was not associated with clinic or ABPM-defined hypertension overall, but most metrics of higher phosphorus intake were associated with lower odds of sustained hypertension compared to sustained normotension, white-coat hypertension, and masked hypertension. There were no associations between dietary phosphorus and nocturnal BP dipping. CONCLUSIONS: These data do not support a role for higher phosphorus intake and higher BP in African Americans.

Association of psychosocial factors with leukocyte telomere length among African Americans in the Jackson Heart Study.

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.

Relation of multi-marker panel to incident chronic kidney disease and rapid kidney function decline in African Americans: the Jackson Heart Study.

BACKGROUND: Few investigations have evaluated the incremental usefulness of multiple biomarkers representing varying physiological pathways for predicting risk of renal outcomes in African Americans. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: We related a multi-marker panel to incident chronic kidney disease (CKD) and rapid kidney function decline (RKFD) in 2813 Jackson Heart Study participants without prevalent CKD at exam 1 (2000-2004) and with complete assays at exam 1 for 9 biomarkers: adiponectin, aldosterone, B-natriuretic peptide [BNP], cortisol, high sensitivity C-reactive protein (hsCRP), endothelin, homocysteine, plasma renin activity and mass. Incident CKD was defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 at exam 3 while RKFD was defined as eGFR ≥30% loss between exams 1 and 3 (8.2 median years). We employed multiple logistic regression model to describe association between the panel and incident CKD and RKFD and used backward elimination strategy to estimate the most parsimonious biomarker model while controlling for conventional risk factors. RESULTS: The multi-marker panel predicted the risk for both incident CKD (odds ratios [OR], 2.72; 95% confidence intervals [CI], 1.63, 4.56; P = 0.001) and RKFD (2.61; 95% CI, 1.67, 4.08; P < 0.001). Per standard deviation increase in log biomarker concentrations were significantly (multivariable adjusted odds ratios, [95% confidence interval], p-value) associated with incident CKD: plasma adiponectin (1.24 [1.07, 1.44], p = 0.005) and leptin (1.3 [1.06, 1.61], p = 0.011), and with RKFD: plasma adiponectin (1.22 [1.06, 1.40], p = 0.006); hsCRP (1.17 [1.01, 1.36], p = 0.031) and aldosterone (0.85 [0.74, 0.96], p = 0.012). Moderate levels (3rd quartile) of aldosterone were inversely associated with incident CKD (0.54 [0.35, 0.82], p = 0.004) while leptin was associated with RKFD (1.64 [1.10, 2.44], p = 0.015). Biomarkers improved CKD risk prediction (P = 0.003) but not RKFD risk prediction (P = 0.10). CONCLUSION: In this community-based sample of African Americans, a multi-marker panel added only moderate predictive improvement compared to conventional risk factors.

Harmonization of Respiratory Data From 9 US Population-Based Cohorts: The NHLBI Pooled Cohorts Study.

Chronic lower respiratory diseases (CLRDs) are the fourth leading cause of death in the United States. To support investigations into CLRD risk determinants and new approaches to primary prevention, we aimed to harmonize and pool respiratory data from US general population-based cohorts. Data were obtained from prospective cohorts that performed prebronchodilator spirometry and were harmonized following 2005 ATS/ERS standards. In cohorts conducting follow-up for noncardiovascular events, CLRD events were defined as hospitalizations/deaths adjudicated as CLRD-related or assigned relevant administrative codes. Coding and variable names were applied uniformly. The pooled sample included 65,251 adults in 9 cohorts followed-up for CLRD-related mortality over 653,380 person-years during 1983-2016. Average baseline age was 52 years; 56% were female; 49% were never-smokers; and racial/ethnic composition was 44% white, 22% black, 28% Hispanic/Latino, and 5% American Indian. Over 96% had complete data on smoking, clinical CLRD diagnoses, and dyspnea. After excluding invalid spirometry examinations (13%), there were 105,696 valid examinations (median, 2 per participant). Of 29,351 participants followed for CLRD hospitalizations, median follow-up was 14 years; only 5% were lost to follow-up at 10 years. The NHLBI Pooled Cohorts Study provides a harmonization standard applied to a large, US population-based sample that may be used to advance epidemiologic research on CLRD.

Intentional and unintentional medication non-adherence in African Americans: Insights from the Jackson Heart Study.

BACKGROUND: Non-adherence to medications is common and leads to suboptimal outcomes. Non-adherence can be intentional (e.g., deciding to skip dosages) or unintentional (e.g., forgetting), yet few studies have distinguished these reasons. An improved understanding of the reasons for non-adherence could inform the development of effective interventions. METHODS AND RESULTS: We analyzed data from African Americans in the Jackson Heart Study who were prescribed medications for one or more chronic conditions. Participants were grouped by patient-reported adherence with non-adherence categorized as being intentional, unintentional or both. We used modified Poisson regression models to examine the factors associated with types of non-adherence. Of 2933 participants taking medication, 2138 (72.9%) reported non-adherence with 754 (35.3%) reporting only unintentional non-adherence, 263 (12.3%) only intentional non-adherence, and 1121 (52.4%) both. Factors independently associated with intentional non-adherence included female sex and depressive symptoms while factors associated with unintentional non-adherence included younger age and separated relationship status. Unintentional and intentional non-adherence was more common among participants taking anti-arrhythmic and anti-asthmatic medications, respectively. Higher levels of global perceived stress was associated with both types of non-adherence. The adjusted models for intentional and unintentional non-adherence had c-statistics of 0.65 and 0.66, respectively, indicating modest discrimination. CONCLUSION: Specific patient factors and individual medication classes were associated with distinct patterns of intentional and unintentional non-adherence, yet the overall modest discrimination of the models suggests contributions from other unmeasured factors. These findings provide a construct for understanding reasons for non-adherence and provide rationale to assess whether personalized interventions can improve adherence.

Masked hypertension and kidney function decline: the Jackson Heart Study.

BACKGROUND: Hypertension diagnosed by blood pressure (BP) measured in the clinic is associated with rapid kidney function decline (RKFD) and incident chronic kidney disease (CKD). The extent to which hypertension defined using out-of-clinic BP measurements is associated with these outcomes is unclear. METHODS: We evaluated the association of any masked hypertension (daytime SBP/DBP ≥ 135/85 mmHg, night-time SBP/DBP ≥ 120/70 mmHg or 24-h SBP/DBP ≥ 130/80 mmHg) with RKFD and incident CKD among 676 African-Americans in the Jackson Heart Study with clinic-measured SBP/DBP less than 140/90 mmHg who completed ambulatory BP monitoring in 2000-2004. RKFD was defined as a decline in estimated glomerular filtration rate (eGFR) at least 30% and incident CKD was defined as development of eGFR less than 60 ml/min per 1.73 m with an at least 25% decline in eGFR between 2000-2004 and 2009-2013. RESULTS: The mean age of participants was 57.6 years, 28.8% were men and 52.7% had any masked hypertension. After a median follow-up of 8 years, 13.8 and 8.6% of participants had RKFD and incident CKD, respectively. In unadjusted analyses, masked hypertension was associated with an increased odds for incident CKD [odds ratio (OR) 2.20, 95% confidence interval (CI) 1.22, 3.97]. This association remained statistically significant after adjustment for demographic characteristics, baseline eGFR and albumin-to-creatinine ratio (OR 1.95, 95% CI 1.04, 3.67) but was eliminated after propensity score adjustment (OR 1.62, 95% CI 0.87, 3.00). There was no association between masked hypertension and RKFD. CONCLUSION: Masked hypertension may be associated with the development of CKD in African-Americans.

Relation of uric acid level to rapid kidney function decline and development of kidney disease: The Jackson Heart Study.

Whether elevated uric acid (UA) is an independent risk factor for chronic kidney disease (CKD) is not well established. The authors evaluated the relationship of UA with rapid kidney function decline (RKFD) and incident CKD among 3702 African Americans (AAs) in the Jackson Heart Study with serum UA levels measured at baseline exam (2000-2004). RKFD was defined as ≥ 30% eGFR loss and incident CKD as development of eGFR < 60 mL/min/1.73 m2 with a ≥ 25% decline in eGFR between baseline and exam 3 (2009-2013). RKFD and CKD were found in 11.4% and 7.5% of the participants, respectively. In a fully adjusted model, the odds of RKFD (OR, 1.8; 95% CI, 1.25-2.49) and incident CKD (OR, 2.00; 95% CI, 1.31-3.06) were significantly higher among participants in the top UA quartile vs bottom quartile. In the JHS, elevated UA was significantly associated with RKFD and incident CKD.

Validation of Risk Equations for Complications of Type 2 Diabetes (RECODe) Using Individual Participant Data From Diverse Longitudinal Cohorts in the U.S.

OBJECTIVE: We sought to validate Risk Equations for Complications of Type 2 Diabetes (RECODe) among diverse populations. RESEARCH DESIGN AND METHODS: We compared risk predictions from RECODe equations and from two alternative risk models (UK Prospective Diabetes Study Outcomes Model 2 [UKPDS OM2] and American College of Cardiology/American Heart Association Pooled Cohort Equations) to observed outcomes in two studies: the Multi-Ethnic Study of Atherosclerosis (MESA, n = 1,555 adults with type 2 diabetes, median follow-up 9.1 years) and the Jackson Heart Study (JHS, n = 1,746 adults with type 2 diabetes, median follow-up 8.0 years). Outcomes included nephropathy by multiple measures (microalbuminuria, macroalbuminuria, renal failure, end-stage renal disease, and reduction in glomerular filtration rate), moderate to severe diabetic retinopathy by Airlie House classification, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, congestive heart failure, and all-cause mortality. RESULTS: RECODe equations for microvascular and cardiovascular outcomes had C-statistics for discrimination ranging from 0.71 to 0.85 in MESA and 0.64 to 0.91 in JHS for alternative outcomes. Calibration slopes in MESA ranged from 0.62 for a composite nephropathy outcome, 0.83-1.04 for individual nephropathy outcomes, 1.07 for retinopathy, 1.00-1.05 for cardiovascular outcomes, and 1.03 for all-cause mortality. Slopes in JHS ranged from 0.47 for retinopathy, 0.97-1.16 for nephropathy, 0.72-1.05 for cardiovascular outcomes, and 1.01 for all-cause mortality. The alternative models had C-statistics 0.50-0.72 and calibration slopes 0.07-0.60. CONCLUSIONS: RECODe equations improved risk estimation for diverse patients with type 2 diabetes, as compared with two commonly used alternatives.

Obesity and synergistic risk factors for chronic kidney disease in African American adults: the Jackson Heart Study.

Background: African Americans are at high risk for chronic kidney disease (CKD). Obesity may increase the risk for CKD by exacerbating features of the metabolic syndrome and promoting glomerular hyperfiltration. Whether other factors also affecting these pathways may amplify or mitigate obesity-CKD associations has not been investigated. Methods: We studied interactions between obesity and these candidate factors in 2043 African Americans without baseline kidney disease enrolled in the Jackson Heart Study. We quantified obesity as body mass index (BMI), sex-normalized waist circumference and visceral adipose volume measured by abdominal computed tomography at an interim study visit. Interactions were hypothesized with (i) metabolic risk factors (dietary quality and physical activity, both quantified by concordance with American Heart Association guidelines) and (ii) factors exacerbating or mitigating hyperfiltration (dietary protein intake, APOL1 risk status and use of renin-angiotensin system blocking medications). Using multivariable regression, we evaluated associations between obesity measures and incident CKD over the follow-up period, as well as interactions with metabolic and hyperfiltration factors. Results: Assessed after a median of 8 years (range 6-11 years), baseline BMI and waist circumference were not associated with incident CKD. Higher visceral adipose volume was independently associated with incident CKD (P = 0.008) in a nonlinear fashion, but this effect was limited to those with lower dietary quality (P = 0.001; P-interaction = 0.04). In additional interaction models, higher waist circumference was associated with greater risk of incident CKD among those with the low-risk APOL1 genotype (P = 0.04) but not those with a high-risk genotype (P-interaction = 0.02). Other proposed factors did not modify obesity-CKD associations. Conclusions. Higher risks associated with metabolically active visceral adipose volume and interactions with dietary quality suggest that metabolic factors may be key determinants of obesity-associated CKD risk. Interactions between obesity and APOL1 genotype should be considered in studies of African Americans.

Gene-by-Psychosocial Factor Interactions Influence Diastolic Blood Pressure in European and African Ancestry Populations: Meta-Analysis of Four Cohort Studies.

Inter-individual variability in blood pressure (BP) is influenced by both genetic and non-genetic factors including socioeconomic and psychosocial stressors. A deeper understanding of the gene-by-socioeconomic/psychosocial factor interactions on BP may help to identify individuals that are genetically susceptible to high BP in specific social contexts. In this study, we used a genomic region-based method for longitudinal analysis, Longitudinal Gene-Environment-Wide Interaction Studies (LGEWIS), to evaluate the effects of interactions between known socioeconomic/psychosocial and genetic risk factors on systolic and diastolic BP in four large epidemiologic cohorts of European and/or African ancestry. After correction for multiple testing, two interactions were significantly associated with diastolic BP. In European ancestry participants, outward/trait anger score had a significant interaction with the C10orf107 genomic region (p = 0.0019). In African ancestry participants, depressive symptom score had a significant interaction with the HFE genomic region (p = 0.0048). This study provides a foundation for using genomic region-based longitudinal analysis to identify subgroups of the population that may be at greater risk of elevated BP due to the combined influence of genetic and socioeconomic/psychosocial risk factors.

Leukocyte telomere length and cardiovascular disease in African Americans: The Jackson Heart Study.

BACKGROUND AND AIMS: In European descent populations, shorter leukocyte telomere length (LTL) has been associated with subclinical atherosclerosis, cardiovascular disease (CVD), and mortality, while longer LTL has been associated with greater left ventricular hypertrophy. We evaluated the relationship of LTL with subclinical cardiovascular disease indices and incident clinical events and mortality in African Americans (AAs). METHODS: Analyses were restricted to 2518 participants of the Jackson Heart Study (JHS) with LTL measured by Southern blot in baseline blood samples. RESULTS: Adjusting for established CVD risk factors, longer LTL was significantly associated with lower prevalence of coronary artery calcification (CAC) (odds ratio (OR) = 0.810) per 1 kb increase in LTL; (95% confidence interval [CI] 0.656, 0.9998), p=0.0498). Longer LTL was also associated with higher ankle brachial index (ABI) (ß = 0.023; (95% CI 0.004, 0.042), p=0.017) when comparing the highest to the lowest LTL quartile. There were no significant associations between LTL and abdominal aortic calcification, carotid intima-media thickness, or left ventricular mass. After a median follow-up of 9 years, longer LTL was associated with lower risk of incident ischemic stroke (hazard ratio (HR) 0.69 (95% CI 0.48, 0.99), p=0.044) and total mortality (HR 0.81 (95% CI 0.67, 0.97), p=0.026) in age and sex adjusted models, but these associations were no longer significant in fully adjusted models. CONCLUSIONS: Among a community-based cohort of AAs, longer LTL was nominally associated with lower odds of CAC and increased ABI, indicative of decreased prevalence of subclinical atherosclerosis and peripheral arterial disease. These findings do not offer strong support for LTL as an independent biomarker of CVD risk in AAs.

Cardiovascular Disease Burden and Socioeconomic Correlates: Findings From the Jackson Heart Study.

BACKGROUND: Black persons have an excess burden of cardiovascular disease (CVD) compared with white persons. This burden persists after adjustment for socioeconomic status and other known CVD risk factors. This study evaluated the CVD burden and the socioeconomic gradient of CVD among black participants in the JHS (Jackson Heart Study). METHODS AND RESULTS: CVD burden was evaluated by comparing the observed prevalence of myocardial infarction, stroke, and hypertension in the JHS at baseline (2000-2004) with the expected prevalence according to US national surveys during a similar time period. The socioeconomic gradient of CVD was evaluated using logistic regression models. Compared with the national data, the JHS age- and sex-standardized prevalence ratios for myocardial infarction, stroke, and hypertension were 1.07 (95% CI, 0.90-1.27), 1.46 (95% CI, 1.18-1.78), and 1.51 (95% CI, 1.42-1.60), respectively, in men and 1.50 (95% CI, 1.27-1.76), 1.33 (95% CI, 1.12-1.57), and 1.43 (95% CI, 1.37-1.50), respectively, in women. A significant and inverse relationship was observed between socioeconomic status and CVD within the JHS cohort. The strongest and most consistent socioeconomic correlate after adjusting for age and sex was income for myocardial infarction (odds ratio: 3.53; 95% CI, 2.31-5.40) and stroke (odds ratio: 3.73; 95% CI, 2.32-5.97), comparing the poor and affluent income categories. CONCLUSIONS: Except for myocardial infarction in men, CVD burden in the JHS cohort was higher than expected. A strong inverse socioeconomic gradient of CVD was also observed within the JHS cohort.

Subclinical Atherosclerosis, Statin Eligibility, and Outcomes in African American Individuals: The Jackson Heart Study.

Importance: Modern prevention guidelines substantially increase the number of individuals who are eligible for treatment with statins. Efforts to refine statin eligibility via coronary calcification have been studied in white populations but not, to our knowledge, in large African American populations. Objective: To compare the relative accuracy of US Preventive Services Task Force (USPSTF) and American College of Cardiology/American Heart Association (ACC/AHA) recommendations in identifying African American individuals with subclinical and clinical atherosclerotic cardiovascular disease (ASCVD). Design, Setting, and Participants: In this prospective, community-based study, 2812 African American individuals aged 40 to 75 years without prevalent ASCVD underwent assessment of ASCVD risk. Of these, 1743 participants completed computed tomography. Main Outcomes and Measures: Nonzero coronary artery calcium (CAC) score, abdominal aortic calcium score, and incident ASCVD (ie, myocardial infarction, ischemic stroke, or fatal coronary heart disease). Results: Of the 2812 included participants, the mean (SD) age at baseline was 55.4 (9.4) years, and 1837 (65.3%) were female. The USPSTF guidelines captured 404 of 732 African American individuals (55.2%) with a CAC score greater than 0; the ACC/AHA guidelines identified 507 individuals (69.3%) (risk difference, 14.1%; 95% CI, 11.2-17.0; P < .001). Statin recommendation under both guidelines was associated with a CAC score greater than 0 (odds ratio, 5.1; 95% CI, 4.1-6.3; P < .001). While individuals indicated for statins under both guidelines experienced 9.6 cardiovascular events per 1000 patient-years, those indicated under only ACC/AHA guidelines were at low to intermediate risk (4.1 events per 1000 patient-years). Among individuals who were statin eligible by ACC/AHA guidelines, the 10-year ASCVD incidence per 1000 person-years was 8.1 (95% CI, 5.9-11.1) in the presence of CAC and 3.1 (95% CI, 1.6-5.9) without CAC (P = .02). While statin-eligible individuals by USPSTF guidelines did not have a significantly higher 10-year ASCVD event rate in the presence of CAC, African American individuals not eligible for statins by USPSTF guidelines had a higher ASCVD event rate in the presence of CAC (2.8 per 1000 person-years; 95% CI, 1.5-5.4) relative to without CAC (0.8 per 1000 person-years; 95%, CI 0.3-1.7) (P = .03). Conclusions and Relevance: The USPSTF guidelines focus treatment recommendations on 38% of high-risk African American individuals at the expense of not recommending treatment in nearly 25% of African American individuals eligible for statins by ACC/AHA guidelines with vascular calcification and at low to intermediate ASCVD risk.