Faculty Bibliography

Metabolic syndrome (MetS) has become a health and financial burden worldwide. The MetS definition captures clustering of risk factors that predict higher risk for diabetes mellitus and cardiovascular disease. Our study hypothesis is that additional to genes influencing individual MetS risk factors, genetic variants exist that influence MetS and inflammatory markers forming a predisposing MetS genetic network. To test this hypothesis a staged approach was undertaken. (a) We analyzed 17 metabolic and inflammatory traits in more than 85,500 participants from 14 large epidemiological studies within the Cross Consortia Pleiotropy Group. Individuals classified with MetS (NCEP definition), versus those without, showed on average significantly different levels for most inflammatory markers studied. (b) Paired average correlations between 8 metabolic traits and 9 inflammatory markers from the same studies as above, estimated with two methods, and factor analyses on large simulated data, helped in identifying 8 combinations of traits for follow-up in meta-analyses, out of 130,305 possible combinations between metabolic traits and inflammatory markers studied. (c) We performed correlated meta-analyses for 8 metabolic traits and 6 inflammatory markers by using existing GWAS published genetic summary results, with about 2.5 million SNPs from twelve predominantly largest GWAS consortia. These analyses yielded 130 unique SNPs/genes with pleiotropic associations (a SNP/gene associating at least one metabolic trait and one inflammatory marker). Of them twenty-five variants (seven loci newly reported) are proposed as MetS candidates. They map to genes MACF1, KIAA0754, GCKR, GRB14, COBLL1, LOC646736-IRS1, SLC39A8, NELFE, SKIV2L, STK19, TFAP2B, BAZ1B, BCL7B, TBL2, MLXIPL, LPL, TRIB1, ATXN2, HECTD4, PTPN11, ZNF664, PDXDC1, FTO, MC4R and TOMM40. Based on large data evidence, we conclude that inflammation is a feature of MetS and several gene variants show pleiotropic genetic associations across phenotypes and might explain a part of MetS correlated genetic architecture. These findings warrant further functional investigation.

BACKGROUND:Heart failure (HF) is a major source of morbidity and mortality, particularly among the elderly. Magnesium, phosphorus, and calcium are micronutrients traditionally viewed in relation to bone health or chronic kidney disease. However, they also may be associated with risk of cardiovascular disease through a broad range of physiologic roles. OBJECTIVE:With the use of data from the Atherosclerosis Risk in Communities (ARIC) cohort, we tested the hypotheses that the incidence of HF is greater among individuals with low serum magnesium and those with high serum phosphorus and calcium. DESIGN/METHODS:A total of 14,709 African Americans (27%) and whites from the ARIC cohort [aged 45-64 y at baseline (1987-1989)] were observed through 2009. Proportional hazards regression was used to explore associations between biomarkers and incident HF. Serum calcium was corrected for serum albumin. Models were adjusted for demographics, behaviors, and physiologic characteristics. RESULTS:A total of 2250 incident HF events accrued over a median follow-up of 20.6 y. Participants in the lowest (≤1.4 mEq/L) compared with the highest (≥1.8 mEq/L) category of magnesium were at greater HF risk (HR: 1.71; 95% CI: 1.46, 1.99). For phosphorus, there appeared to be a threshold whereby only those in the highest quintile were at greater HF risk [HR(Q5 vs Q1): 1.34; 95% CI: 1.16, 1.54]. Higher concentrations of calcium were also associated with greater risk of HF [HR(Q5 vs Q1): 1.24; 95% CI: 1.07, 1.43]. Results were not modified by race, sex, or kidney function and were similar when incident coronary heart disease was included as a time-varying covariate. CONCLUSIONS:Low serum magnesium and high serum phosphorus and calcium were independently associated with greater risk of incident HF in this population-based cohort. Whether these biomarkers will be useful candidates for HF risk prediction or targets for prevention remains to be seen.

BACKGROUND:According to a recent meta-analysis, parathyroid hormone (PTH) excess is associated with increased cardiovascular disease (CVD) risk, but existing studies are limited. We examined in a prospective study the association of PTH with the incidence of CVD, taking into account vitamin D and other confounding variables. METHODS:The ARIC study measured PTH using a second-generation assay (Roche, Indianapolis, IN) in stored serum samples from 1990 to 1992 and related levels in 10,392 adults to incident cardiovascular outcomes (coronary heart disease [n = 808], heart failure [n = 1,294], stroke [n = 586], peripheral artery disease [n = 873], atrial fibrillation [n = 1,190], and CVD mortality [n = 647]) through 2010 (median follow-up 19 years). RESULTS:Contrary to the hypothesis, PTH level was not associated positively with any CVD outcome. The associations of incident heart failure, peripheral artery disease, and CVD mortality with PTH actually were weakly inverse (P trend = .02-.04) in the most fully adjusted models. For example, the hazard ratios across PTH quartiles were 1.00, 1.07, 1.07, and 0.96 (P trend = .74) for coronary heart disease incidence and were 1.00, 0.69, 0.74, and 0.74 (P trend = .02) for CVD mortality. Patterns were similar when restricted to participants with normal baseline kidney function. CONCLUSIONS:This large prospective study failed to support the hypothesis that elevated PTH is an independent risk marker for incident CVD. When our data were added to the previous meta-analysis, the pooled hazard ratio remained statistically significant but weakened.

BACKGROUND:The extent to which the relative contributions of traditional cardiovascular risk factors to incident cardiovascular disease (CVD) may have changed over time remains unclear. METHODS AND RESULTS/RESULTS:We studied 13 541 participants (56% women, 26% black) in the Atherosclerosis Risk in Communities Study, aged 52 to 66 years and free of CVD at exams in 1987 through 1989, 1990 through 1992, 1993 through 1995, or 1996 through 1998. At each examination, we estimated the population attributable risks (PAR) of traditional risk factors (hypertension, diabetes mellitus, obesity, hypercholesterolemia, and smoking) for the 10-year incidence of CVD. Overall, the PAR of all risk factors combined appeared to decrease from the late 1980s to the late 1990s (0.58 to 0.53). The combined PAR was higher in women than men in 1987 through 1989 (0.68 versus 0.51, P<0.001) but not by the late 1990s (0.58 versus 0.48, P=0.08). The combined PAR was higher in blacks than whites in the late 1980s (0.67 versus 0.57, P=0.049), and this difference was more pronounced by the late 1990s (0.67 versus 0.48, P=0.002). By the late 1990s, the PAR of hypertension had become higher in women than men (P=0.02) and also appeared higher in blacks than whites (P=0.08). By the late 1990s, the PAR of diabetes mellitus remained higher in women than men (P<0.0001) and in blacks than whites (P<0.0001). CONCLUSIONS:The contribution to CVD of all traditional risk factors combined is greater in blacks than whites, and this difference may be increasing. The contributions of hypertension and diabetes mellitus remain especially high, in women as well as blacks. These findings underscore the continued need for individual as well as population approaches to CVD risk factor modification.

BACKGROUND:Few reports have shown an association between access type and inflammatory marker levels in a longitudinal cohort. We investigated the role of access type on serial levels of inflammatory markers and the role of inflammatory markers in mediating the association of access type and risk of mortality in a prospective study of incident dialysis patients. STUDY DESIGN/METHODS:Cohort study, post hoc analysis of the CHOICE (Choices for Healthy Outcomes in Caring for ESRD) Study. SETTING & PARTICIPANTS/METHODS:In 583 participants, inflammation was assessed by measuring serum C-reactive protein (CRP) and interleukin 6 (IL-6) after access placement and at multiple times during 3 years' follow-up. Type of access was categorized as central venous catheter (CVC), arteriovenous graft (AVG), and arteriovenous fistula (AVF), and changes over time were recorded. PREDICTOR/METHODS:Access type, age, sex, race, body mass index, diabetes, cardiovascular disease, and serum albumin level. OUTCOMES/RESULTS:CRP level, IL-6 level, and mortality. MEASUREMENTS/METHODS:We used mixed-effects pattern mixture models to study the association between access type and repeated measurements of inflammation and survival analysis to investigate the association of access type and mortality, adjusting for predictors. RESULTS:In a mixed-effects pattern mixture model, compared with AVFs, the presence of CVCs and AVGs was associated with 62% (P=0.02) and 30% (P=0.05) increases in average CRP levels, respectively. A Cox proportional hazards model yielded nonsignificant associations of CVC and AVG use (vs AVFs) with risk of mortality when adjusted for inflammatory marker levels. Higher CRP levels were associated with increased risk of CVC failure than lower CRP levels. LIMITATIONS/CONCLUSIONS:CRP and IL-6 measurements not performed for all hemodialysis patients. CONCLUSIONS:CVCs, compared with AVFs, are associated with a greater state of inflammation in incident hemodialysis patients, and the association of catheter use and mortality may be mediated by access-induced inflammation. Our findings support recommendations for the early removal or avoidance of CVC placements.

BACKGROUND:Increased concentrations of circulating fibroblast growth factor 23 (FGF-23) have been associated with higher risk of cardiovascular disease. The association between FGF-23 and the risk of atrial fibrillation (AF), a common arrhythmia, is less defined. Thus, we explored whether FGF-23 concentration was associated with AF incidence in a large community-based cohort. METHODS AND RESULTS/RESULTS:We studied 12 349 men and women enrolled in the Atherosclerosis Risk in Communities (ARIC) study, without prevalent AF at baseline in 1990-1992. Serum intact FGF-23 concentration was measured with the Kainos 2-site ELISA. Incident AF through 2010 was ascertained from study ECGs and hospital discharge codes. Cox proportional hazards models adjusted for potential confounding factors, including kidney function, were used to estimate the association between FGF-23 and AF risk. We identified 1572 AF events during a mean follow-up of 17 years. In multivariable analysis, a difference of 1 SD (16 pg/mL) in baseline FGF-23 was not associated with the risk of AF (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.99, 1.09). Results were similar when FGF-23 was modeled in quartiles (HR, 1.09; 95% CI, 0.94, 1.26, comparing extreme quartiles). Reduced kidney function was associated with increased AF risk across quartiles of FGF-23 levels. CONCLUSION/CONCLUSIONS:In this large community-based cohort, baseline FGF-23 levels were not associated with AF risk independently of kidney function. Our results do not support a major role for FGF-23 as a risk factor for AF or as a mediator of the association between chronic kidney disease and AF.

BACKGROUND:Lower estimated glomerular filtration rate (eGFR) on a single occasion is associated with risk of cardiovascular events; whether the degree of change in eGFR during a 1-year period adds prognostic information is unknown. METHODS AND RESULTS/RESULTS:We included adults who had ≥2 outpatient eGFR measurements (≥6 months apart) during a 1-year accrual period in Alberta, Canada. According to recent guidelines, we used a change in eGFR category (≥90, 60 to 89, 45 to 59, 30 to 44, 15 to 29, and <15 mL/min per 1.73 m(2)), and the presence/absence of a ≥25% change from baseline to classify participants into 5 groups: certain drop, uncertain drop, stable (no change), uncertain rise, and certain rise. We calculated adjusted rates of cardiovascular events (per 10 000 person-years) for each group. We estimated the adjusted risks of cardiovascular events associated with each category of change in eGFR, in reference to stable kidney function. Among the 526 388 participants, 76.1% (n=400 560) had stable, 2.6% (n=13 668) had a certain drop, and 3.3% (n=17 499) had a certain rise in eGFR. Compared with participants with stable kidney function, adjusted risks of myocardial infarction, heart failure, and stroke were 27%, 51%, and 20% higher, respectively, for those with a certain drop in kidney function. After adjusting for the last eGFR at the end of the accrual period, the observed association diminished. CONCLUSION/CONCLUSIONS:Clinically relevant changes in eGFR are associated with increased risk of cardiovascular events. However, most of the apparent increase in risk can be accounted for by assessing comorbidity and baseline kidney function.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Novel biomarkers that more accurately reflect kidney function and predict future CKD are needed. The human metabolome is the product of multiple physiologic or pathophysiologic processes and may provide novel insight into disease etiology and progression. This study investigated whether estimated kidney function would be associated with multiple metabolites and whether selected metabolomic factors would be independent risk factors for incident CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS/METHODS:In total, 1921 African Americans free of CKD with a median of 19.6 years follow-up among the Atherosclerosis Risk in Communities Study were included. A total of 204 serum metabolites quantified by untargeted gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry was analyzed by both linear regression for the cross-sectional associations with eGFR (specified by the Chronic Kidney Disease Epidemiology Collaboration equation) and Cox proportional hazards model for the longitudinal associations with incident CKD. RESULTS:Forty named and 34 unnamed metabolites were found to be associated with eGFR specified by the Chronic Kidney Disease Epidemiology Collaboration equation with creatine and 3-indoxyl sulfate showing the strongest positive (2.8 ml/min per 1.73 m(2) per +1 SD; 95% confidence interval, 2.1 to 3.5) and negative association (-14.2 ml/min per 1.73 m(2) per +1 SD; 95% confidence interval, -17.0 to -11.3), respectively. Two hundred four incident CKD events with a median follow-up time of 19.6 years were included in the survival analyses. Higher levels of 5-oxoproline (hazard ratio, 0.70; 95% confidence interval, 0.60 to 0.82) and 1,5-anhydroglucitol (hazard ratio, 0.68; 95% confidence interval, 0.58 to 0.80) were significantly related to lower risk of incident CKD, and the associations did not appreciably change when mutually adjusted. CONCLUSIONS:These data identify a large number of metabolites associated with kidney function as well as two metabolites that are candidate risk factors for CKD and may provide new insights into CKD biomarker identification.

BACKGROUND:Although obesity is an independent risk factor for heart failure (HF), once HF is established, obesity is associated with lower mortality. It is unclear if the weight loss due to advanced HF leads to this paradoxical finding. OBJECTIVES/OBJECTIVE:This study sought to evaluate the prognostic impact of pre-morbid obesity in patients with HF. METHODS:In the ARIC (Atherosclerosis Risk In Communities) study, we used body mass index (BMI) measured ≥6 months before incident HF (pre-morbid BMI) to evaluate the association of overweight (BMI 25 to <30 kg/m(2)) and obesity (BMI ≥30 kg/m(2)) compared with normal BMI (18.5 to <25 kg/m(2)) with mortality after incident HF. RESULTS:Among 1,487 patients with incident HF, 35% were overweight and 47% were obese by pre-morbid BMI measured 4.3 ± 3.1 years before HF diagnosis. Over 10-year follow-up after incident HF, 43% of patients died. After adjustment for demographics and comorbidities, being pre-morbidly overweight (hazard ratio [HR]: 0.72; 95% confidence interval [CI]: 0.58 to 0.90; p = 0.004) or obese (HR: 0.70; 95% CI: 0.56 to 0.87; p = 0.001) had a protective association with survival compared with normal BMI. The protective effect of overweight and obesity was consistent across subgroups on the basis of a history of cancer, smoking, and diabetes. CONCLUSIONS:Our results, for the first time, demonstrate that patients who were overweight or obese before HF development have lower mortality after HF diagnosis compared with normal BMI patients. Thus, weight loss due to advanced HF may not completely explain the protective effect of higher BMI in HF patients.

OBJECTIVE:Traditional predictors suboptimally predict cardiovascular disease (CVD) in individuals with chronic kidney disease (CKD). This study compared 5 nontraditional cardiac and kidney markers on the improvement of cardiovascular prediction among those with CKD. APPROACH AND RESULTS/RESULTS:Among 8622 participants aged 52 to 75 years in the Atherosclerosis Risk in Communities (ARIC) Study, cardiac troponin T, N-terminal pro-B-type natriuretic peptide, cystatin C, β2-microglobulin, and β-trace protein were compared for improvement in predicting incident CVD after stratifying by CKD status (940 participants with CKD [kidney dysfunction or albuminuria]). During a median follow-up of 11.9 years, there were 1672 CVD events including coronary disease, stroke, and heart failure (336 cases in CKD). Every marker was independently associated with incident CVD in participants with and without CKD. The adjusted hazard ratios (per 1 SD) were larger for cardiac markers than for kidney markers, particularly in CKD (1.61 [95% confidence interval, 1.43-1.81] for cardiac troponin T, 1.50 [1.34-1.68] for N-terminal pro-B-type natriuretic peptide, and <1.26 for kidney markers). Particularly in CKD group, cardiac markers compared with kidney markers contributed to greater c-statistic increment (0.032-0.036 versus 0.012-0.015 from 0.679 with only conventional predictors in CKD and 0.008-0.011 versus 0.002-0.010 from 0.697 in non-CKD) and categorical net reclassification improvement (0.086-0.127 versus 0.020-0.066 in CKD and 0.057-0.077 versus 0.014-0.048 in non-CKD). The superiority of cardiac markers was largely consistent in individual CVD outcomes. CONCLUSIONS:A greater improvement in cardiovascular prediction was observed for cardiac markers than for kidney markers in people with CKD. These results suggest that cardiac troponin T and N-terminal pro-B-type natriuretic peptide are useful for better CVD risk classification in this population.