Genome-wide association study of serum metabolites in the African American Study of Kidney Disease and Hypertension.

The genome-wide association study (GWAS) is a powerful means to study genetic determinants of disease traits and generate insights into disease pathophysiology. To date, few GWAS of circulating metabolite levels have been performed in African Americans with chronic kidney disease. Hypothesizing that novel genetic-metabolite associations may be identified in a unique population of African Americans with a lower glomerular filtration rate (GFR), we conducted a GWAS of 652 serum metabolites in 619 participants (mean measured glomerular filtration rate 45 mL/min/1.73m2) in the African American Study of Kidney Disease and Hypertension, a clinical trial of blood pressure lowering and antihypertensive medication in African Americans with chronic kidney disease. We identified 42 significant variant metabolite associations. Twenty associations had been previously identified in published GWAS, and eleven novel associations were replicated in a separate cohort of 818 African Americans with genetic and metabolomic data from the Atherosclerosis Risk in Communities Study. The replicated novel variant-metabolite associations comprised eight metabolites and eleven distinct genomic loci. Nine of the replicated associations represented clear enzyme-metabolite interactions, with high expression in the kidneys as well as the liver. Three loci (ACY1, ACY3, and NAT8) were associated with a common pool of metabolites, acetylated amino acids, but with different individual affinities. Thus, extensive metabolite profiling in an African American population with chronic kidney disease aided identification of novel genome-wide metabolite associations, providing clues about substrate specificity and the key roles of enzymes in modulating systemic levels of metabolites.

Association Between Midlife Physical Activity and Incident Kidney Disease: The Atherosclerosis Risk in Communities (ARIC) Study.

RATIONALE & OBJECTIVE: Physical activity is associated with lower risk for cardiovascular disease, diabetes, and hypertension, which have shared risk factor profiles with chronic kidney disease (CKD). However, there are conflicting findings regarding the relationship between physical activity and CKD. The objective was to evaluate the association between physical activity and CKD development over long-term follow-up using the Atherosclerosis Risk in Communities (ARIC) Study. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 14,537 participants aged 45 to 64 years. PREDICTORS: Baseline physical activity status was assessed using the modified Baecke Physical Activity Questionnaire at visit 1 (1987-1989) and categorized according to the 2018 Physical Activity Guidelines for Americans to group participants as inactive, insufficiently active, active, and highly active. OUTCOMES: Incident CKD defined as estimated glomerular filtration rate (eGFR)<60mL/min/1.73m2 at follow-up and≥25% decline in eGFR relative to baseline, CKD-related hospitalization or death, or initiation of kidney replacement therapy. ANALYTICAL APPROACH: Cox proportional hazards regression. RESULTS: At baseline, 37.8%, 24.2%, 22.7%, and 15.3% of participants were classified as inactive, insufficiently active, active, and highly active, respectively. During a median follow-up of 24 years, 33.2% of participants developed CKD. After adjusting for age, sex, race-center, education, smoking status, diet quality, diabetes, coronary heart disease, hypertension, antihypertensive medication, body mass index, and baseline eGFR, higher categories of physical activity were associated with lower risk for CKD compared with the inactive group (HRs for insufficiently active, 0.95 [95% CI, 0.88-1.02]; active, 0.93 [95% CI, 0.86-1.01]; highly active, 0.89 [95% CI, 0.81-0.97]; P for trend = 0.007). LIMITATIONS: Observational design and self-reported physical activity that was based on leisure time activity only. Due to low numbers, participants who were not Black or White were excluded. CONCLUSIONS: Highly active participants had lower risk for developing CKD compared with inactive participants.

Association and impact of hypertension defined using the 2017 AHA/ACC guidelines on the risk of atrial fibrillation in The Atherosclerosis Risk in Communities study.

BACKGROUND: Hypertension is an established risk factor for the development of atrial fibrillation (AF). We evaluated the association and population impact of hypertension, defined using the new 2017 guidelines, on risk of AF. METHODS: In this analysis, we included 14,915 participants in the Atherosclerosis Risk in Communities study without history of AF. Participants underwent blood pressure measurements at baseline and their antihypertensive medication use was assessed. Incident AF was ascertained from study electrocardiograms, hospital records and death certificates. Cox proportional models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) of AF among individuals with hypertension based on the JNC7 and 2017 ACC/AHA guidelines. Poisson models were used to obtain risk ratios and calculate population-attributable fractions (PAFs). RESULTS: We identified 2891 cases of incident AF during 21.4 years of mean follow-up. Prevalence of hypertension was 34 and 48% under the JNC7 and 2017 ACC/AHA definitions, respectively. HRs (95%CI) of AF in hypertensives versus non-hypertensives were 1.44 (1.32, 1.56) and 1.37 (1.26, 1.48) after multivariable adjustment under the old and new guidelines, respectively. The corresponding PAF (95%CI) using the old and new guidelines were 11% (8, 13%) and 13% (9, 16%), respectively. CONCLUSIONS: Overall, our analysis shows that even though the prevalence of hypertension using the new criteria is 40% higher than with the old criteria, this does not translate into meaningful increases in AF attributable to hypertension. These results suggest that prevention or treatment of hypertension based on the new (versus old) guidelines may have limited impact on AF incidence.

Meta-analysis across Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium provides evidence for an association of serum vitamin D with pulmonary function.

The role that vitamin D plays in pulmonary function remains uncertain. Epidemiological studies reported mixed findings for serum 25-hydroxyvitamin D (25(OH)D)-pulmonary function association. We conducted the largest cross-sectional meta-analysis of the 25(OH)D-pulmonary function association to date, based on nine European ancestry (EA) cohorts (n 22 838) and five African ancestry (AA) cohorts (n 4290) in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Data were analysed using linear models by cohort and ancestry. Effect modification by smoking status (current/former/never) was tested. Results were combined using fixed-effects meta-analysis. Mean serum 25(OH)D was 68 (sd 29) nmol/l for EA and 49 (sd 21) nmol/l for AA. For each 1 nmol/l higher 25(OH)D, forced expiratory volume in the 1st second (FEV1) was higher by 1·1 ml in EA (95 % CI 0·9, 1·3; P<0·0001) and 1·8 ml (95 % CI 1·1, 2·5; P<0·0001) in AA (P race difference=0·06), and forced vital capacity (FVC) was higher by 1·3 ml in EA (95 % CI 1·0, 1·6; P<0·0001) and 1·5 ml (95 % CI 0·8, 2·3; P=0·0001) in AA (P race difference=0·56). Among EA, the 25(OH)D-FVC association was stronger in smokers: per 1 nmol/l higher 25(OH)D, FVC was higher by 1·7 ml (95 % CI 1·1, 2·3) for current smokers and 1·7 ml (95 % CI 1·2, 2·1) for former smokers, compared with 0·8 ml (95 % CI 0·4, 1·2) for never smokers. In summary, the 25(OH)D associations with FEV1 and FVC were positive in both ancestries. In EA, a stronger association was observed for smokers compared with never smokers, which supports the importance of vitamin D in vulnerable populations.

Social relationships, amyloid burden, and dementia: The ARIC-PET study.

INTRODUCTION: This study aimed to assess whether social relationships in mid-life reduce the risk of dementia related to amyloid burden. METHODS: Participants in the Atherosclerosis Risk in Communities (ARIC) study were assessed for social support and isolation (visit 2; 1990-1992). A composite measure, "social relationships," was generated. Brain amyloid was evaluated with florbetapir positron emission tomography (PET); (visit 5; 2012-2014). Incident dementia cases were identified following visit 5 through 2019 using ongoing surveillance. Relative contributions of mid-life social relationships and elevated brain amyloid to incident dementia were evaluated with Cox regression models. RESULTS: Among 310 participants without dementia, strong mid-life social relationships were associated independently with lower dementia risk. Elevated late-life brain amyloid was associated with greater dementia risk. DISCUSSION: Although mid-life social relationships did not moderate the relationship between amyloid burden and dementia, these findings affirm the importance of strong social relationships as a potentially protective factor against dementia.

Association between cognitive impairment and risk of atrial fibrillation: The Atherosclerosis Risk in Communities study.

BACKGROUND: Atrial fibrillation (AF) is reportedly a risk factor for cognitive impairment. Interestingly, recent studies have emphasized that impaired cognition is probably an initiating factor of cardiovascular disease. Thus, we aimed to explore the association between impaired cognition and the risk of AF, and clarify the potential mechanisms. METHODS: Participants of visit 2 (1991-1993) in the Atherosclerosis Risk in Communities study were included. Global cognition z-scores and factor scores were calculated using the word fluency, delayed word recall, and digit symbol substitution tests. AF incidents were diagnosed by electrocardiography and inpatient records. The association of cognitive decline with AF risk and left atrial volume index (LAVI) was explored using Cox proportional hazards and linear regression models, respectively. RESULTS: During the median follow-up of 18.2 ± 6.2 years, 2056/11,675 (17.6%) participants developed AF. Participants in the lowest quartile of global cognition z- and factor scores had a higher risk of AF (hazard ratio [HR]: 1.271, 95% confidence interval [CI]: 1.094-1.477, p = 0.002; HR: 1.305, 95% CI: 1.110-1.535, p = 0.001, respectively) than those in the highest quartile. Global cognition z- and factor scores were negatively correlated with the LAVI (B: -0.411, 95% CI: -0.749 to -0.074, p = 0.017; B: -0.425, 95% CI: -0.833 to -0.017, p = 0.041, respectively). CONCLUSION: S: : Cognitive decline is significantly associated with a higher risk of AF, with atrial remodeling being a potential mechanism. Our results extend previous findings of the brain-heart axis and indicate the effects of cognitive injury on cardiac function and structure. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; unique identifier: NCT00005131.

Number of prior live births is associated with higher arterial stiffness but not its change in older women: the atherosclerosis risk in communities study.

Introduction: Although studies have demonstrated a J-shaped association between parity and cardiovascular disease (CVD), the association with arterial stiffness is not fully understood. Methods: We examined the association between parity and carotid-femoral pulse wave velocity (cfPWV), a measure of central arterial stiffness. We conducted a longitudinal analysis of 1220 women (mean age 73.7 years) who attended the Atherosclerosis Risk in Communities Study visit 5 (2011-2013). At visit 2 (1990-1992), women self-reported parity (number of prior live births), which we categorized as: 0 (never pregnant or pregnant with no live births); 1-2 (referent); 3-4; and 5+ live births. Technicians measured cfPWV at visit 5 (2011-2013) and visit 6 or 7 (2016-2019). Multivariable linear regression modeled the associations of parity with visit 5 cfPWV and cfPWV change between visit 5 and 6/7 adjusted for demographics and potential confounding factors. Results: Participants reported 0 (7.7%), 1-2 (38.7%), 3-4 (40.0%), or 5+ (13.6%) prior live births. In adjusted analyses, women with 5+ live births had a higher visit 5 cfPWV (ß=50.6 cm/s, 95% confidence interval: 3.6, 97.7 cm/s) than those with 1-2 live births. No statistically significant associations were observed for other parity groups with visit 5 cfPWV or with cfPWV change. Discussion: In later life, women with 5+ live births had higher arterial stiffness than those with 1-2 live births, but cfPWV change did not differ by parity, suggesting women with 5+ live births should be targeted for early primary prevention of CVD given their higher arterial stiffness at later-life.

Cognition impairment and risk of subclinical cardiovascular disease in older adults: The atherosclerosis risk in communities study.

Background: Clinical cardiovascular disease (CVD) and cognition impairment are common and often coexist in aging populations, and CVD is associated with greater cognition impairment risk; however, the association between cognition impairment and CVD risk is inconsistent. It is unknown if pathways that contribute to CVD are caused by impaired cognition. We hypothesized that cognition impairment would be associated with greater subclinical CVD including subclinical myocardial damage [assessed by high-sensitivity cardiac troponin T (hs-cTnT)] and cardiac strain or dysfunction [assessed by N-terminal pro-B-type natriuretic peptide (NT-proBNP)]. Methods: This analysis included Atherosclerosis Risk in Communities Study (ARIC) participants who underwent global cognition z-score tests between 1991 and 1993. Cardiac biomarkers were measured from stored plasma samples collected between 1996 and 1999. Logistic regression models were used to determine the association of cognitive function with subclinical CVD risk. Results: There were 558/9216 (6.1%) and 447/9097 (5.0%) participants with incident elevated hs-CTnT (≥14 ng/L) and NT-proBNP (≥300 pg/mL) levels, respectively. Comparing the lowest and highest quartiles of global cognition z-scores, a higher incidence of elevated hs-CTnT [odds ratio (OR) = 1.511, 95% confidence interval (CI): 1.093-2.088, P = 0.013] and NT-proBNP (OR = 1.929, 95% CI: 1.350-2.755, P < 0.001) were observed, respectively. In structural equation modeling, the indirect effect of global cognition z-score on major adverse cardiac events was 42.1% (P < 0.05). Conclusion: Impairments in baseline cognitive function were associated with subclinical myocardial damage or wall strain. Although future studies are warranted to investigate the pathophysiological mechanisms behind these associations, our study suggests common pathways between cognitive and cardiac dysfunction.

Prevalence and Prognostic Significance of Mitral Regurgitation in Acute Decompensated Heart Failure: The ARIC Study.

OBJECTIVES: This study investigates the prevalence and prognostic significance of mitral regurgitation (MR) in acute decompensated heart failure (ADHF) patients. BACKGROUND: Few studies characterize the burden of MR in heart failure. METHODS: The ARIC (Atherosclerosis Risk In Communities) study surveilled ADHF hospitalizations for residents ≥55 years of age in 4 U.S. communities. ADHF cases were stratified by left ventricular ejection fraction (LVEF): <50% and ≥50%. Odds of moderate or severe MR in patients with varying sex and race, and odds of 1-year mortality in those with higher MR severity were estimated using multivariable logistic regression. RESULTS: From 2005 to 2014, there were 17,931 weighted ADHF hospitalizations of which 49.2% had an LVEF <50% and 50.8% an LVEF ≥50%. Moderate or severe MR prevalence was 44.5% in those with an LVEF <50% and 27.5% in those with an LVEF ≥50%. Moderate or severe MR was more likely in females than males regardless of LVEF; LVEF <50% (odds ratio [OR]: 1.21 [95% confidence interval (CI): 1.11 to 1.33]), LVEF ≥50% (OR: 1.52 [95% CI: 1.36 to 1.69]). Among hospitalizations with an LVEF ≥50%, moderate or severe MR was less likely in blacks than whites (OR: 0.72 [95% CI: 0.64 to 0.82]). Higher MR severity was independently associated with increased 1-year mortality in those with an LVEF <50% (OR: 1.30 [95% CI: 1.16 to 1.45]). CONCLUSIONS: Patients with ADHF have a significant MR burden that varies with sex and race. In ADHF patients with an LVEF <50%, higher MR severity is associated with excess 1-year mortality.

Greater Adherence to Life's Simple 7 Is Associated With Less Arterial Stiffness: the Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: Greater arterial stiffness is associated independently with increased cardiovascular disease risk. The American Heart Association (AHA) has recommended following "Life's Simple 7 (LS7)" to optimize cardiovascular health; we tested whether better LS7 in middle age is associated with less arterial stiffness in later life. METHODS: We studied 4,232 black and white participants aged 45-64 years at the baseline (1987-89) visit of the Atherosclerosis Risk in Communities Study cohort who also had arterial stiffness measured in 2011-13 (mean ± SD interval: 23.6 ± 1.0 years). We calculated a 14-point summary score for baseline LS7 and classified participants as having "poor" (0-4), "average" (5-9), or "ideal" (10-14) cardiovascular health. We used logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (95% CI) for arterial stiffening: a high carotid-femoral pulse wave velocity (cfPWV, ≥13.23 m/s) or a high central pulse pressure (central PP, ≥ 82.35 mm Hg). RESULTS: The age, race, sex, and heart rate-adjusted ORs (95% CI) for high cfPWV in the "ideal," "average," and "poor" LS7 summary categories were 1 (Reference), 1.30 (1.11, 1.53), and 1.68 (1.10,2.56), respectively (P-trend = 0.0003). Similarly, the adjusted ORs (95% CI) for high central PP across LS7 summary categories were 1 (Reference), 1.48 (1.27, 1.74), and 1.63 (1.04, 2.56), respectively (P-trend <0.0001). CONCLUSION: Greater LS7 score in middle age is associated with less arterial stiffness 2-3 decades later. These findings further support the AHA recommendation to follow LS7 for cardiovascular disease prevention.

Longitudinal increases in blood biomarkers of inflammation or cardiovascular disease and the incidence of venous thromboembolism.

Essentials Inflammatory and cardiac diseases are associated with increased venous thromboembolism (VTE) risk. Our prospective study assessed rise in inflammatory or cardiac biomarkers and VTE risk. A greater 6-year rise in N-terminal natriuretic peptide is associated with increased VTE incidence. Volume overload or impending cardiac disease may contribute to VTE occurrence. SUMMARY: Background We previously showed that participants in the population-based Atherosclerosis Risk in Communities (ARIC) cohort with elevated levels of blood biomarkers of inflammation or cardiac disease were at increased risk of venous thromboembolism (VTE). Objective We hypothesized that ARIC participants with larger 6-year increases in the levels of three biomarkers - C-reactive protein (CRP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and troponin T - would also have an increased subsequent risk of VTE. Methods We measured changes in the levels of these biomarkers in 9844 participants from 1990-1992 to 1996-1998, and then identified VTEs through 2015. Results A greater 6-year rise in the level of NT-proBNP, but not in that of CRP or troponin T, was significantly associated with increased VTE incidence over a median of 17.6 years of follow-up. After adjustment for other VTE risk factors, those whose NT-proBNP level rose from < 100 pg mL-1 to ≥ 100 pg mL-1 had a hazard ratio for VTE of 1.44 (95% confidence interval [CI] 1.15-1.80), as compared with the reference group with an NT-proBNP level of < 100 pg mL-1 at both times. This hazard ratio was slightly higher (1.66, 95% CI 1.19-2.31) during the first 10 years of follow-up, but was attenuated (1.24, 95% CI 0.99-1.56) after adjustment for prevalent and incident coronary heart disease, heart failure, and atrial fibrillation. Conclusions The two most likely explanations for our results are that: (i) an increasing NT-proBNP level reflects increasing subclinical volume overload and potentially increased venous stasis or subclinical PE that had gone unrecognized over time; or (ii) an increasing NT-proBNP level is a risk marker for impending cardiac disease that places patients at risk of VTE.

Lipoprotein associated phospholipase A2 activity, apolipoprotein C3 loss-of-function variants and cardiovascular disease: The Atherosclerosis Risk In Communities Study.

OBJECTIVE: Lipoprotein-associated phospholipase A2 (LpPLA2) activity was associated with higher CHD risk in a meta-analysis, which was partly dependent on circulating lipid levels. Apolipoprotein C3 loss-of-function (ApoC3 LOF) mutations were related with reduced postprandial lipemia and CHD risk. However, the association of LpPLA2 activity with ApoC3 LOF is not known. METHODS: We examined the association of LpPLA2 activity and ApoC3 LOF mutations and incident cardiovascular disease (CVD) (defined as coronary heart disease [CHD] plus ischemic stroke) and all-cause mortality in the biracial longitudinal Atherosclerosis Risk In Communities (ARIC) study. RESULTS: The mean LpPLA2 activity was 229.3 nmol/min/mL and was higher in men and whites. LpPLA2 activity correlated positively with atherogenic dyslipidemia. ApoC3 LOF carriers had lower LpPLA2 activity levels compared to non-carriers, and there was inverse association between LpPLA2 activity and ApoC3 LOF mutations in whites. In a fully adjusted model, greater LpPLA2 activity was independently associated with incident CVD (HR 1.35, 1.09-1.68 for highest vs. lowest quintile), which was mainly explained by its association with CHD, and was also associated with all-cause mortality (HR 1.65, 1.38-1.98). CONCLUSIONS: Greater LpPLA2 activity was associated with increased CHD and all-cause mortality in both whites and African-Americans in the ARIC study. The inverse relation between LpPLA2 activity and ApoC3 LOF mutations suggests that delayed lipoprotein clearance may at least in part explain the observed association of LpPLA2 activity with increased CVD risk.

The 25-hydroxyvitamin D3 C-3 epimer: distribution, correlates, and reclassification of 25-hydroxyvitamin D status in the population-based Atherosclerosis Risk in Communities Study (ARIC).

BACKGROUND: Little is known about the vitamin D3 epimer [3-epi-25(OH)D3], particularly in adults. We describe characteristics of the D3 epimer within the community-based ARIC cohort. METHODS: The vitamin D3 epimer, 25(OH)D3, and 25(OH)D2 were measured using LC-MS/MS in stored serum collected in 1990-1992 from 9,887 white and 3,221 black ARIC study participants, aged 46-70years. Cross-sectional characteristics were explored. RESULTS: Concentrations of the epimer were quantifiable (≥1.41ng/ml) in 33.4% of whites and 15.0% of blacks and made up on average 3.23% and 2.25% of total D3 [epimer+25(OH)D3] concentrations, respectively. Epimer levels were positively correlated with 25(OH)D3 in both whites (r=0.54) and blacks (r=0.36) and were unrelated to 25(OH)D2 concentrations. Overall, epimer levels were associated with participant characteristics in a manner similar to that typically observed for 25(OH)D3. Including the epimer in the calculation of total 25(OH)D resulted in approximately 2% of participants being reclassified from being clinically 25(OH)D deficient to having suboptimal levels. CONCLUSIONS: Low concentrations of the D3 epimer were present in adult serum and overall the epimer concentration is moderately correlated with the 25(OH)D3 concentration. The reclassification of participant's clinical 25(OH)D status upon inclusion of the epimer was minimal.

Variation in the checkpoint kinase 2 gene is associated with type 2 diabetes in multiple populations.

Identification and characterization of the genetic variants underlying type 2 diabetes susceptibility can provide important understanding of the etiology and pathogenesis of type 2 diabetes. We previously identified strong evidence of linkage for type 2 diabetes on chromosome 22 among 3,383 Hypertension Genetic Epidemiology Network (HyperGEN) participants from 1,124 families. The checkpoint 2 (CHEK2) gene, an important mediator of cellular responses to DNA damage, is located 0.22 Mb from this linkage peak. In this study, we tested the hypothesis that the CHEK2 gene contains one or more polymorphic variants that are associated with type 2 diabetes in HyperGEN individuals. In addition, we replicated our findings in two other Family Blood Pressure Program (FBPP) populations and in the population-based Atherosclerosis Risk in Communities (ARIC) study. We genotyped 1,584 African-American and 1,531 white HyperGEN participants, 1,843 African-American and 1,569 white GENOA participants, 871 African-American and 1,009 white GenNet participants, and 4,266 African-American and 11,478 white ARIC participants for four single nucleotide polymorphisms (SNPs) in CHEK2. Using additive models, we evaluated the association of CHEK2 SNPs with type 2 diabetes in participants within each study population stratified by race, and in a meta-analysis, adjusting for age, age(2), sex, sex-by-age interaction, study center, and relatedness. One CHEK2 variant, rs4035540, was associated with an increased risk of type 2 diabetes in HyperGEN participants, two replication samples, and in the meta-analysis. These results may suggest a new pathway in the pathogenesis of type 2 diabetes that involves pancreatic beta-cell damage and apoptosis.