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1.  Longitudinal association between serum urate and subclinical atherosclerosis: the Coronary Artery Risk Development in Young Adults (CARDIA) study 
Journal of internal medicine  2013;274(6):10.1111/joim.12120.
Objective
The aim of the present study was to determine whether serum urate (sUA) concentration is positively associated with subclinical atherosclerosis, independent of body mass index (BMI), among generally healthy adults.
Design and setting
The CARDIA study followed 5115 black and white individuals aged 18–30 years in 1985–1986 (year 0). Subclinical atherosclerosis comprised coronary artery calcified plaque (CAC; years 15, 20 and 25) and maximum common carotid intima–media thickness (IMT; year 20). sUA (years 0, 10, 15 and 20) was modelled as gender-specific quartiles that were pooled. Discrete-time hazard regressions and generalized linear regressions were used for analyses.
Results
Mean sUA concentration was lower in women than in men, and increased with age. Adjusting for demographic and lifestyle factors, the highest versus lowest quartile of sUA at year 0 was associated with a 44% [95% confidence interval (CI) 20%, 73%] greater risk of CAC progression from year 15 to 25 (Ptrend < 0.001), which was attenuated by adjustment for BMI at year 0 (Ptrend = 0.45). A stronger association was found between sUA at year 15 and CAC progression at year 20 or 25 (hazard ratio 2.07, 95% CI 1.66, 2.58 for the highest versus lowest sUA quartile Ptrend < 0.001), which was attenuated but remained significant with additional adjustment for BMI at year 15 (Ptrend = 0.01). A greater increment in sUA concentration from year 0 to year 15, independent of change in BMI, was related to a higher risk of CAC progression (Ptrend < 0.001). Similar associations were found between sUA and IMT, but only in men.
Conclusion
sUA may be an early biomarker for subclinical atherosclerosis in young adults; starting in early middle age, sUA predicts subclinical atherosclerosis independently of BMI.
doi:10.1111/joim.12120
PMCID: PMC3825786  PMID: 23952533
calcified plaque; intima–media thickness; subclinical atherosclerosis; urate; uric acid
2.  Changes in waist circumference and body mass index in the US CARDIA cohort: Fixed-effect associations with self-reported experiences of racial/ethnic discrimination 
Journal of biosocial science  2012;45(2):267-278.
Prior studies examining the association between self-reported experiences of racial/ethnic discrimination and obesity have had mixed results and primarily been cross-sectional. This study tests the hypothesis that an increase in self-reported experiences of racial/ethnic discrimination predicts gains in waist circumference and body mass index in Black and White women and men over eight years. In race/ethnicity- and gender-stratified models, this study examined whether change in self-reported experiences of racial/ethnic discrimination predicts changes in waist circumference and body mass index over time using a fixed-effect regression approach in SAS statistical software, providing control for both measured and unmeasured time-invariant covariates. Between 1992–93 and 2000–01, self-reported experiences of racial/ethnic discrimination decreased among 843 Black women (75% to 73%), 601 Black men (80% to 77%), 893 White women (30% to 23%), and 856 White men (28% to 23%). In fixed-effect regression models, controlling for all time-invariant covariates, social desirability bias, and changes in education and parity (women only) over time, an increase in self-reported experiences of racial/ethnic discrimination over time was significantly associated with an increase in waist circumference (b=1.09, 95% CI: 0.00–2.19, p=0.05) and an increase in body mass index (b=0.67, 95% CI: 0.19–1.16, p=0.007) among Black women. No associations were observed among Black men and White women and men. These findings suggest that an increase in self-reported experiences of racial/ethnic discrimination may be associated with increases in waist circumference and body mass index among Black women over time.
doi:10.1017/S0021932012000429
PMCID: PMC4310212  PMID: 22856616
3.  Relation of Left Ventricular Mass at Age 23 to 35 years to Global Left Ventricular Systolic Function 20 Years Later (From the Coronary Artery Risk Development in Young Adults Study) 
The American journal of cardiology  2013;113(2):377-383.
Left ventricular (LV) mass and LV ejection fraction (EF) are major independent predictors of future cardiovascular disease. The association of LV mass with future LVEF in younger populations has not been studied. We investigated the relation of LV mass index (LVMI) at age 23 to 35 years to LV function after 20 years of follow-up in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. CARDIA is a longitudinal study that enrolled young adults in 1985–1986. We included participants with echocardiographic examinations at both years-5 and -25. LVMI and LVEF were assessed using M-mode echocardiography at year-5 and using both M-mode and 2-dimensional images at year-25. Statistical analytic models assessed the correlation between LVMI and LV functional parameters both cross-sectionally and longitudinally. A total of 2,339 participants were included. The mean LVEF at year-25 was 62%. Although there was no cross-sectional correlation between LVMI and LVEF at year-5, there was a small, but statistically significant negative correlation between LVMI at year-5 and LVEF 20 years later (r = −0.10, p < 0.0001); this inverse association persisted for LVMI in the multivariable model. High LVMI was an independent predictor of systolic dysfunction (LVEF < 50%) 20 years later (odds ratio 1.46, p = 0.0018). In conclusion, we have shown that LVMI in young adulthood in association with chronic risk exposure impacts systolic function in middle age; the antecedents of heart failure may occur at younger ages than previously thought.
doi:10.1016/j.amjcard.2013.08.052
PMCID: PMC3901209  PMID: 24176073
left ventricular mass; left ventricular ejection fraction; echocardiography; left ventricular remodeling
4.  Genetic loci associated with circulating levels of very long-chain saturated fatty acids[S] 
Journal of Lipid Research  2015;56(1):176-184.
Very long-chain saturated fatty acids (VLSFAs) are saturated fatty acids with 20 or more carbons. In contrast to the more abundant saturated fatty acids, such as palmitic acid, there is growing evidence that circulating VLSFAs may have beneficial biological properties. Whether genetic factors influence circulating levels of VLSFAs is not known. We investigated the association of common genetic variation with plasma phospholipid/erythrocyte levels of three VLSFAs by performing genome-wide association studies in seven population-based cohorts comprising 10,129 subjects of European ancestry. We observed associations of circulating VLSFA concentrations with common variants in two genes, serine palmitoyl-transferase long-chain base subunit 3 (SPTLC3), a gene involved in the rate-limiting step of de novo sphingolipid synthesis, and ceramide synthase 4 (CERS4). The SPTLC3 variant at rs680379 was associated with higher arachidic acid (20:0 , P = 5.81 × 10−13). The CERS4 variant at rs2100944 was associated with higher levels of 20:0 (P = 2.65 × 10−40) and in analyses that adjusted for 20:0, with lower levels of behenic acid (P = 4.22 × 10−26) and lignoceric acid (P = 3.20 × 10−21). These novel associations suggest an inter-relationship of circulating VLSFAs and sphingolipid synthesis.
doi:10.1194/jlr.M052456
PMCID: PMC4274065  PMID: 25378659
arachidic acid; behenic acid; lignoceric acid; sphingolipids
5.  Methylomics of gene expression in human monocytes 
Human Molecular Genetics  2013;22(24):5065-5074.
DNA methylation is one of several epigenetic mechanisms that contribute to the regulation of gene expression; however, the extent to which methylation of CpG dinucleotides correlates with gene expression at the genome-wide level is still largely unknown. Using purified primary monocytes from subjects in a large community-based cohort (n = 1264), we characterized methylation (>485 000 CpG sites) and mRNA expression (>48K transcripts) and carried out genome-wide association analyses of 8370 expression phenotypes. We identified 11 203 potential cis-acting CpG loci whose degree of methylation was associated with gene expression (eMS) at a false discovery rate threshold of 0.001. Most of the associations were consistent in effect size and direction of effect across sex and three ethnicities. Contrary to expectation, these eMS were not predominately enriched in promoter regions, or CpG islands, but rather in the 3′ UTR, gene bodies, CpG shores or ‘offshore’ sites, and both positive and negative correlations between methylation and expression were observed across all locations. eMS were enriched for regions predicted to be regulatory by ENCODE (Encyclopedia of DNA Elements) data in multiple cell types, particularly enhancers. One of the strongest association signals detected (P < 2.2 × 10−308) was a methylation probe (cg17005068) in the promoter/enhancer region of the glutathione S-transferase theta 1 gene (GSTT1, encoding the detoxification enzyme) with GSTT1 mRNA expression. Our study provides a detailed description of the epigenetic architecture in human monocytes and its relationship to gene expression. These data may help prioritize interrogation of biologically relevant methylation loci and provide new insights into the epigenetic basis of human health and diseases.
doi:10.1093/hmg/ddt356
PMCID: PMC3836482  PMID: 23900078
6.  Acetylcholinesterase Activity and Neurodevelopment in Boys and Girls 
Pediatrics  2013;132(6):e1649-e1658.
BACKGROUND:
Organophosphate exposures can affect children’s neurodevelopment, possibly due to neurotoxicity induced by acetylcholinesterase (AChE) inhibition, and may affect boys more than girls. We tested the hypothesis that lower AChE activity is associated with lower neurobehavioral development among children living in Ecuadorian floricultural communities.
METHODS:
In 2008, we examined 307 children (age: 4–9 years; 52% male) and quantified AChE activity and neurodevelopment in 5 domains: attention/executive functioning, language, memory/learning, visuospatial processing, and sensorimotor (NEPSY-II test). Associations were adjusted for demographic and socioeconomic characteristics and height-for-age, flower worker cohabitation, and hemoglobin concentration.
RESULTS:
Mean ± standard deviation AChE activity was 3.14 ± 0.49 U/mL (similar for both genders). The range of scores among neurodevelopment subtests was 5.9 to 10.7 U (standard deviation: 2.6–4.9 U). Girls had a greater mean attention/executive functioning domain score than boys. In boys only, there were increased odds ratios of low (<9th percentile) neurodevelopment among those in the lowest tertile versus the highest tertile of AChE activity (odds ratios: total neurodevelopment: 5.14 [95% confidence interval (CI): 0.84 to 31.48]; attention/executive functioning domain: 4.55 [95% CI: 1.19 to 17.38], memory/learning domain: 6.03 [95% CI: 1.17 to 31.05]) after adjustment for socioeconomic and demographic factors, height-for-age, and hemoglobin. Within these domains, attention, inhibition and long-term memory subtests were most affected.
CONCLUSIONS:
Low AChE activity was associated with deficits in neurodevelopment, particularly in attention, inhibition, and memory in boys but not in girls. These critical cognitive skills affect learning and academic performance. Added precautions regarding secondary occupational pesticide exposure would be prudent.
doi:10.1542/peds.2013-0108
PMCID: PMC3838526  PMID: 24249815
acetylcholinesterase; AChE; ADD; ADHD; agriculture; agricultural communities; attention; boys; children; Ecuador; floriculture; flower; girls; growth; inhibition; inhibitory control; memory; neurobehavioral development; neurodevelopment; plantation; pesticide
7.  Evaluating the Framingham Hypertension Risk Prediction Model in Young Adults: The Coronary Artery Risk Development in Young Adults (CARDIA) Study 
Hypertension  2013;62(6):1015-1020.
A prediction model was developed in the Framingham Heart Study (FHS) to evaluate short-term risk of hypertension. Our goal was to determine the predictive ability of the FHS hypertension model in a cohort of young adults advancing into middle age and compare it with the predictive ability of prehypertension, and individual components of the FHS model. We studied 4,388 participants, age 18-30 years without hypertension at baseline, enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) Study who participated in 2 consecutive exams occurring 5 years apart between the baseline (1985-1986) and Year 25 examination (2010-2011). Weibull regression was used to assess the association of the FHS model overall, individual components of the FHS model, and prehypertension with incident hypertension. Over the 25 year follow-up period, 1179 participants developed incident hypertension. The FHS hypertension model (c-index=0.84, 95% CI=0.83, 0.85) performed well in discriminating those who did and did not develop hypertension and was better than prehypertension alone (c-index=0.71, 95% CI=0.70, 0.73). The predicted risk from the FHS hypertension model was systematically lower than the observed hypertension incidence initially (χ2= 249.4; p<0.001), but demonstrated a good fit after recalibration (χ2= 14.6; p=0.067). In summary, the FHS model performed better than prehypertension and may be a useful tool for identifying young adults with a high risk for developing hypertension.
doi:10.1161/HYPERTENSIONAHA.113.01539
PMCID: PMC4019674  PMID: 24041951
hypertension; prehypertension; epidemiology; risk
8.  Subclinical Atherosclerotic Calcification and Cognitive Functioning in Middle-Aged Adults: The CARDIA Study 
Atherosclerosis  2013;231(1):10.1016/j.atherosclerosis.2013.08.038.
Objective
Cardiovascular risk factors in middle-age are associated with cognitive impairment and dementia in older age. Less is known about the burden of calcified subclinical atherosclerosis and cognition, especially in midlife. We examined the association of coronary artery and abdominal aortic calcified plaque (CAC and AAC, respectively) with cognitive functioning in middle-aged adults.
Methods
This cross-sectional study included 2,510 black and white adults (age: 43–55 years) without heart disease or stroke who completed a year 25 follow-up exam (2010–11) as part of the Coronary Artery Risk Development in Young Adults Study. CAC and AAC were measured with non-contrast computed tomography. Cognition was assessed with the Digit Symbol Substitution Test (DSST) (psychomotor speed), Stroop Test (executive function), and Rey Auditory Verbal Learning Test (RAVLT) (verbal memory).
Results
A greater amount of CAC and AAC was associated with worse performance on each test of cognitive function after adjustment for age, sex, race, education, and study center. Associations were attenuated, but remained significant for the DSST and RAVLT following additional adjustment for vascular risk factors, including adiposity, smoking, alcohol use, dyslipidemia, hypertension, and diabetes. Compared to participants without CAC or AAC, those with both CAC and AAC, but not CAC or AAC alone was associated with lower DSST scores (p<0.05).
Conclusions
In this community-based sample, greater subclinical atherosclerotic calcification was associated with worse psychomotor speed and memory in midlife. These findings underscore the importance of a life course approach to the study of cognitive impairment with aging.
doi:10.1016/j.atherosclerosis.2013.08.038
PMCID: PMC3828555  PMID: 24125414
atherosclerosis; heart disease; calcium score; cognition; subclinical disease; risk factors
9.  Breakfast Frequency and Development of Metabolic Risk 
Diabetes Care  2013;36(10):3100-3106.
OBJECTIVE
The relation of breakfast intake frequency to metabolic health is not well studied. The aim of this study was to examine breakfast intake frequency with incidence of metabolic conditions.
RESEARCH DESIGN AND METHODS
We performed an analysis of 3,598 participants from the community-based Coronary Artery Risk Development in Young Adults (CARDIA) study who were free of diabetes in the year 7 examination when breakfast and dietary habits were assessed (1992–1993) and participated in at least one of the five subsequent follow-up examinations over 18 years.
RESULTS
Relative to those with infrequent breakfast consumption (0–3 days/week), participants who reported eating breakfast daily gained 1.9 kg less weight over 18 years (P = 0.001). In a Cox regression analysis, there was a stepwise decrease in risk across conditions in frequent breakfast consumers (4–6 days/week) and daily consumers. The results for incidence of abdominal obesity, obesity, metabolic syndrome, and hypertension remained significant after adjustment for baseline measures of adiposity (waist circumference or BMI) in daily breakfast consumers. Hazard ratios (HRs) and 95% CIs for daily breakfast consumption were as follows: abdominal obesity HR 0.78 (95% CI 0.66–0.91), obesity 0.80 (0.67–0.96), metabolic syndrome 0.82 (0.69–0.98), and hypertension 0.84 (0.72–0.99). For type 2 diabetes, the corresponding estimate was 0.81 (0.63–1.05), with a significant stepwise inverse association in black men and white men and women but no association in black women. There was no evidence of differential results for high versus low overall dietary quality.
CONCLUSIONS
Daily breakfast intake is strongly associated with reduced risk of a spectrum of metabolic conditions.
doi:10.2337/dc13-0316
PMCID: PMC3781522  PMID: 23775814
10.  No Association of 9p21 with Arterial Elasticity and Retinal Microvascular Findings 
Atherosclerosis  2013;230(2):301-303.
Objective
How 9p21 variation affects risk of cardiovascular disease is unclear, so we assessed whether 9p21 variants are associated with arterial elasticity or retinal microvascular findings.
Methods
In the prospective Multi-Ethnic Study of Atherosclerosis (MESA) we assessed 378 SNPs in the 9p21 locus. Within four ethnic groups, we used an additive genetic model to relate the 9p21 SNPs to five vascular phenotypes: small and large elasticity derived from radial diastolic pulse contour analysis; Young’s elastic modulus from carotid artery ultrasound measurements; and the diameter of the central retinal arteries and veins.
Results
In neither ethnic-specific nor pooled data was there any statistically significant association between any of the 9p21 SNPs and any of the five vascular phenotypes.
Conclusion
Our study does not support an association of 9p21 variation with arterial elasticity or retinal microvascular abnormalities.
doi:10.1016/j.atherosclerosis.2013.07.049
PMCID: PMC3787319  PMID: 24075760
Prospective study; 9p21 SNP; retinal microvascular abnormalities; arterial elasticity
11.  Parathyroid hormone and arterial dysfunction in the Multi-Ethnic Study of Atherosclerosis 
Clinical endocrinology  2013;79(3):429-436.
Objective
High circulating concentrations of parathyroid hormone (PTH) have been associated with increased risks of hypertension, left ventricular hypertrophy, congestive heart failure, and cardiovascular mortality. Impaired arterial function is a potential mechanism for these associations. We tested whether serum PTH concentration is associated with measures of arterial function.
Design
Cross-sectional study.
Participants
6,545 persons without clinical cardiovascular disease participating in the community-based Multi-Ethnic Study of Atherosclerosis.
Measurements
Brachial artery flow-mediated dilation as well as aortic pulse pressure and arterial pulse parameters derived from Windkessel modeling of the radial pressure waveform.
Results
Higher serum PTH concentration was associated with lower brachial artery flow-mediated dilation (mean difference −0.09% per 10 pg/mL PTH), higher aortic pulse pressure (0.53 mmHg per 10 pg/mL), and reduced Windkessel capacitive index C1 (large artery elasticity, −0.12 ml/mmHg X 10 per 10 pg/mL), adjusting for potential confounding variables (all p-values ≤ 0.001). These relationships were independent of serum calcium concentration, serum 25-hydroxyvitamin D concentration, and estimated glomerular filtration rate and were consistent across relevant participant subgroups. Associations of PTH with aortic pulse pressure and capacitive index C1 were attenuated after adjustment for blood pressure. Serum PTH concentration was not associated with the oscillatory index C2 (small artery elasticity).
Conclusions
Higher serum PTH concentration was associated with impaired endothelial function, increased aortic pulse pressure, and decreased capacitive index C1 in a large, diverse, community-based population. These relationships may help explain previously observed associations of elevated PTH with cardiovascular disease.
doi:10.1111/cen.12163
PMCID: PMC3664253  PMID: 23402353
parathyroid hormone; calcium; vitamin D; arterial function; epidemiology
12.  Relation Between Serum Free Fatty Acids and Adiposity, Insulin Resistance, and Cardiovascular Risk Factors From Adolescence to Adulthood 
Diabetes  2013;62(9):3163-3169.
The objective of this study was to describe longitudinal relations of serum total free fatty acids (FFAs) to insulin resistance (IR) and cardiovascular (CV) risk factors from adolescence into adulthood. The cohort included participants in a longitudinal study of obesity and IR with complete data, including anthropometric measures, FFAs, IR measured by euglycemic clamp, blood pressure, fasting serum lipids, and insulin at mean 15 and 22 years of age (n = 207) and their parents (n = 272). FFAs and IR were not significantly related at mean 15 years of age but were significantly related at mean age 22 years. FFA did not relate to BMI at either age. FFA at 15 years of age estimated IR at 22 years of age. In parents (mean age 51 years), FFA was significantly correlated with BMI, percent body fat, systolic blood pressure, LDL, and IR. Associations with all risk factors except IR in parents were attenuated by adjustment for BMI. Most 22 years of age correlations with parents were higher than corresponding 15 years of age correlations. This study finds that FFA is associated with IR starting in young adulthood. The relation between FFA and CV risk factors does not become significant until later adulthood. The results support a significant impact of early metabolic dysfunction on later CV risk.
doi:10.2337/db12-1122
PMCID: PMC3749355  PMID: 23670973
13.  Replication and fine mapping of asthma-associated loci in individuals of African ancestry 
Human genetics  2013;132(9):1039-1047.
Asthma originates from genetic and environmental factors with about half the risk of disease attributable to heritable causes. Genome-wide association studies, mostly in populations of European ancestry, have identified numerous asthma-associated single nucleotide polymorphisms (SNPs). Studies in populations with diverse ancestries allow both for identification of robust associations that replicate across ethnic groups and for improved resolution of associated loci due to different patterns of linkage disequilibrium between ethnic groups. Here we report on an analysis of 745 African-American subjects with asthma and 3,238 African-American control subjects from the Candidate Gene Association Resource (CARe) Consortium, including analysis of SNPs imputed using 1,000 Genomes reference panels and adjustment for local ancestry. We show strong evidence that variation near RAD50/IL13, implicated in studies of European ancestry individuals, replicates in individuals largely of African ancestry. Fine mapping in African ancestry populations also refined the variants of interest for this association. We also provide strong or nominal evidence of replication at loci near ORMDL3/GSDMB, IL1RLML18R1, and 10pl4, all previously associated with asthma in European or Japanese populations, but not at the PYHIN1 locus previously reported in studies of African-American samples. These results improve the understanding of asthma genetics and further demonstrate the utility of genetic studies in populations other than those of largely European ancestry.
doi:10.1007/s00439-013-1310-7
PMCID: PMC3975655  PMID: 23666277
14.  Genome-wide and gene-centric analyses of circulating myeloperoxidase levels in the charge and care consortia 
Human Molecular Genetics  2013;22(16):3381-3393.
Increased systemic levels of myeloperoxidase (MPO) are associated with the risk of coronary artery disease (CAD). To identify the genetic factors that are associated with circulating MPO levels, we carried out a genome-wide association study (GWAS) and a gene-centric analysis in subjects of European ancestry and African Americans (AAs). A locus on chromosome 1q31.1 containing the complement factor H (CFH) gene was strongly associated with serum MPO levels in 9305 subjects of European ancestry (lead SNP rs800292; P = 4.89 × 10−41) and in 1690 AA subjects (rs505102; P = 1.05 × 10−8). Gene-centric analyses in 8335 subjects of European ancestry additionally identified two rare MPO coding sequence variants that were associated with serum MPO levels (rs28730837, P = 5.21 × 10−12; rs35897051, P = 3.32 × 10−8). A GWAS for plasma MPO levels in 9260 European ancestry subjects identified a chromosome 17q22 region near MPO that was significantly associated (lead SNP rs6503905; P = 2.94 × 10−12), but the CFH locus did not exhibit evidence of association with plasma MPO levels. Functional analyses revealed that rs800292 was associated with levels of complement proteins in serum. Variants at chromosome 17q22 also had pleiotropic cis effects on gene expression. In a case–control analysis of ∼80 000 subjects from CARDIoGRAM, none of the identified single-nucleotide polymorphisms (SNPs) were associated with CAD. These results suggest that distinct genetic factors regulate serum and plasma MPO levels, which may have relevance for various acute and chronic inflammatory disorders. The clinical implications for CAD and a better understanding of the functional basis for the association of CFH and MPO variants with circulating MPO levels require further study.
doi:10.1093/hmg/ddt189
PMCID: PMC3723315  PMID: 23620142
15.  Blood Pressure Trajectories in Early Adulthood and Subclinical Atherosclerosis in Middle Age 
Importance
Single measures of blood pressure (BP) levels are associated with the development of atherosclerosis; however, long-term patterns in BP and their impact on CVD risk are poorly characterized.
Objective
To identify common BP trajectories throughout early adulthood and to determine their association with presence of coronary artery calcification (CAC) during middle age.
Design
We used data from the CARDIA study from baseline in 1985-1986 through 25 years of follow-up (2010-2011).
Setting
Prospective cohort study
Participants
CARDIA participants were Black and White men and women aged 18-30 years at baseline.
Exposures
We examined systolic BP, diastolic BP, and mid-BP [calculated as (SBP+DBP)/2 and an important marker of CHD risk among younger populations] at baseline and years 2, 5, 7, 10, 15, 20, and 25. Latent mixture modeling was used to identify trajectories in SBP, DBP and mid-BP over time.
Main Outcome Measure
Coronary artery calcification greater than or equal to Agatston score of 100 Agatston units at year 25.
Results
Among 4,681 participants, we identified 5 distinct mid-BP trajectories: Low-Stable (22% [95% CI 19.9-23.7], n=987), Moderate-Stable (42% [40.3-44.3], n=2,085), Moderate-Increasing (12% [10.4-14.0], n=489), Elevated-Stable (19% [17.1-20.0], n=903) and Elevated-Increasing (5% [4.0-5.5], n=217). As compared to the Low-Stable group, trajectories with elevated BP levels had greater odds of having CAC >100. Adjusted odds ratios (95% CI) were 1.44 (0.83-2.49) for Moderate-Stable, 1.86 (0.91-3.82) for Moderate-Increasing, 2.28 (1.24-3.70) for Elevated-Stable, and 3.70 (1.66-8.20) for Elevated-Increasing groups. The adjusted prevalence of CAC ≥ 100 was 5.8% in the Low-Stable group. These ORs represent an absolute increase of 2.7%, 5%, 6.3% and 12.9% for the prevalence of CAC ≥100 for the Moderate-Stable, Moderate-Increasing, Elevated Stable and Elevated Increasing groups respectively as compared to the Low-Stable Group. Associations were not altered after adjustment for baseline and year 25 BP. Findings were similar for trajectories of isolated systolic BP trajectories, but were attenuated for diastolic BP trajectories.
Conclusions and Relevance
BP trajectories throughout young adulthood vary and higher BP trajectories were associated with an increased risk of CAC in middle age. Long-term trajectories in BP may assist in more accurate identification of individuals with subclinical atherosclerosis.
doi:10.1001/jama.2013.285122
PMCID: PMC4122296  PMID: 24496536
blood pressure; calcium; epidemiology; risk factors
16.  Lifestyle-Related Factors, Obesity, and Incident Microalbuminuria: The CARDIA (Coronary Artery Risk Development in Young Adults) Study 
Background
Modifiable lifestyle-related factors are associated with risk of coronary heart disease and may also influence kidney disease risk.
Study Design
Community-based prospective cohort study.
Setting & Participants
2354 African-American and white participants ages 28–40 years, without baseline microalbuminuria or estimated glomerular filtration rate <60 ml/min/1.73 m2 recruited from four U.S. centers: Birmingham AL, Chicago IL, Minneapolis MN, and Oakland CA.
Factors
Current smoking, physical activity, fast food habits, obesity, and diet quality, which was based on 8 fundamental components of the Dietary Approaches to Stop Hypertension (DASH) diet, including increased intake of fruits, vegetables, low-fat dairy products, whole grains, nuts and legumes, and reduced intake of sodium, sugar sweetened beverages, and red and processed meats.
Outcomes & Measurements
Spot urine albumin-creatinine ratios (ACRs) were obtained at baseline (1995–96) and 3 5-year follow-up examinations (5, 10, and 15 years follow-up). Incident microalbuminuria was defined as presence of race and sex-adjusted ACR ≥25 mg/g at 2 or more of the successive follow-up examinations.
Results
Over the 15-year follow-up period, 77 individuals (3.3%) developed incident microalbuminuria. After multivariable adjustment, poor diet quality (OR, 2.0; 95% CI, 1.1–3.4) and obesity (OR, 1.9; 95% CI, 1.1–3.3) were significantly associated with microalbuminuria; current smoking (OR, 1.6; 95% CI, 0.9–2.8) was associated with microalbuminuria although the CI crossed 1.0. Neither low physical activity (OR, 1.0; 95% CI, 0.5–1.8) nor fast food consumption (OR, 1.2; 95% CI, 0.7–2.3) were associated with microalbuminuria. Compared to individuals with no unhealthy lifestyle-related factors (poor diet quality, current smoking and obesity), adjusted odds of incident microalbuminuria were 131%, 273%, and 634% higher for presence of 1 (OR, 2.3; 95% CI, 1.3–4.3), 2 (OR, 3.7; 95% CI, 1.8–7.7), and 3 (OR, 7.3; 95% CI, 2.1–26.1) unhealthy lifestyle-related factors.
Limitations
Self-reported dietary history and physical activity, low number of outcomes.
Conclusions
Consuming an unhealthy diet and obesity are associated with incident microalbuminuria.
doi:10.1053/j.ajkd.2013.02.363
PMCID: PMC3720776  PMID: 23601954
17.  Estimated Kidney Function Based on Serum Cystatin C and Risk of Subsequent Coronary Artery Calcium in Young and Middle-aged Adults With Preserved Kidney Function: Results From the CARDIA Study 
American Journal of Epidemiology  2013;178(3):410-417.
Whether kidney dysfunction is associated with coronary artery calcium (CAC) in young and middle-aged adults who have a cystatin C–derived estimated glomerular filtration rate (eGFRcys) greater than 60 mL/min/1.73 m2 is unknown. In the Coronary Artery Risk Development in Young Adults (CARDIA) cohort (recruited in 1985 and 1986 in Birmingham, Alabama; Chicago, Illinois; Minneapolis, Minnesota; and Oakland, California), we examined 1) the association of eGFRcys at years 10 and 15 and detectable CAC over the subsequent 5 years and 2) the association of change in eGFRcys and subsequent CAC, comparing those with stable eGFRcys to those whose eGFRcys increased (>3% annually over 5 years), declined moderately (3%–5%), or declined rapidly (>5%). Generalized estimating equation Poisson models were used, with adjustment for age, sex, race, educational level, income, family history of coronary artery disease, diabetes, body mass index, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and tobacco use. Among 3,070 participants (mean age 35.6 (standard deviation, 4.1) years and mean eGFRcys 106.7 (standard deviation, 18.5) mL/min/1.73 m2), 529 had detectable CAC. Baseline eGFRcys was not associated with CAC. Moderate eGFRcys decline was associated with a 33% greater relative risk of subsequent CAC (95% confidence interval: 5, 68; P = 0.02), whereas rapid decline was associated with a 51% higher relative risk (95% confidence interval: 10, 208; P = 0.01) in adjusted models. In conclusion, among young and middle-aged adults with eGFRcys greater than 60 mL/min/1.73 m2, annual decline in eGFRcys is an independent risk factor for subsequent CAC.
doi:10.1093/aje/kws581
PMCID: PMC3816347  PMID: 23813702
calcification; cardiovascular diseases; chronic kidney insufficiency; coronary arteries; coronary disease; cystatin C; glomerular filtration rate; kidney
18.  Dietary supplements and mortality in older women: the Iowa Women's Health Study 
Archives of internal medicine  2011;171(18):1625-1633.
Background
Although dietary supplements are commonly taken to avoid chronic disease, long-term health consequences of many compounds are unknown.
Methods
We assessed the use of vitamin and mineral supplements in relation to total mortality in 38 772 older women in the Iowa Women's Health Study, mean age 61.6 years at baseline in 1986. Supplement use was self-reported in 1986, 1997 and 2004. Through December 31, 2008, 15 594 deaths (40.2%) were identified through the State Health Registry of Iowa and the National Death Index.
Results
In multivariable adjusted proportional hazards regression models, the use of multivitamins (Hazard Ratio (HR), 1.06 [95% CI, 1.02-1.10], Absolute Risk Increase (ARI), 2.4%), vitamin B6 (HR, 1.10 [95% CI, 1.01-1.21], ARI, 4.1%), folic acid (HR, 1.15 [95% CI, 1.00-1.32], ARI, 5.9%), iron (HR, 1.10 [95% CI, 1.03-1.17], ARI, 3.9%), magnesium (HR, 1.08 [95% CI, 1.01-1.15], ARI, 3.6%), zinc (HR, 1.08 [95% CI, 1.01-1.15], ARI, 3.0%) and copper (HR, 1.45 [95% CI, 1.20-1.75], ARI, 18.0%) were associated with increased risk of total mortality when compared with corresponding nonusers, while calcium was inversely related (HR, 0.91 [95% CI, 0.88-0.94], Absolute Risk Reduction (ARR), 3.8%). Findings for iron and calcium were replicated in separate shorter-term analyses (10-year, 6-year and 4-year follow-up) each with about 15% dead, starting in 1986, 1997, and 2004.
Conclusion
In older women several commonly used dietary vitamin and mineral supplements may be associated with increased total mortality risk, most strongly supplemental iron, while calcium, in contrast to many studies, was associated with decreased risk.
doi:10.1001/archinternmed.2011.445
PMCID: PMC4114071  PMID: 21987192
Cohort; Iowa Women's Health study; minerals; supplement; total mortality; vitamins; women
19.  Insulin Resistance, Subclinical Left Ventricular Remodeling, and the Obesity Paradox: The Multi-Ethnic Study of Atherosclerosis 
Objectives
We assessed in the Multi-Ethnic Study of Atherosclerosis (MESA) whether impaired fasting glucose, insulin resistance, and waist-to-hip ratio had effects on cardiac remodeling, independent of obesity.
Background
Recent studies suggest that central obesity and insulin resistance may be primary mediators of obesity-related cardiac remodeling independent of body mass index (BMI).
Methods
We investigated 4,364 individuals without diabetes in MESA. Impaired fasting glucose (IFG: 100-125 mg/dl) or insulin resistance (by homeostatic model assessment of insulin resistance, HOMA-IR) and waist-to-hip ratio (WHR) were used for cardiometabolic phenotyping. Multivariate linear regression analysis was used to determine the effects of the cardiometabolic markers on LV remodeling, assessed primarily through the LV mass-to-volume ratio obtained by cine cardiac magnetic resonance imaging.
Results
Individuals with IFG were more likely to be older, hypertensive, with increased prevalence of cardiometabolic risk factors regardless of BMI. In each quartile of BMI, individuals with above-median HOMA-IR, above-median WHR, or IFG had a higher LV mass-to-volume ratio (p<0.05 for all). HOMA-IR (p<0.0001), WHR (p<0.0001), and the presence of IFG (p=0.04), but not BMI (p=0.24), were independently associated with LV mass-to-volume ratio after adjustment for age, gender, hypertension, race, and dyslipidemia.
Conclusions
Insulin resistance and waist-to-hip ratio are associated with concentric LV remodeling independent of BMI. These results support the emerging hypothesis that the cardiometabolic phenotype, defined by insulin resistance and central obesity, may play a critical role in LV remodeling independently of BMI.
doi:10.1016/j.jacc.2013.01.053
PMCID: PMC4114341  PMID: 23500236
obesity; metabolic syndrome; LV remodeling; MESA
20.  Associations between total serum GGT activity and metabolic risk: MESA 
Biomarkers in medicine  2013;7(5):709-721.
Aim
To evaluate associations between total serum GGT activity, metabolic risk factors and prevalent metabolic disease in MESA.
Patients & methods
Continuous associations between GGT and fasting blood glucose (FBG), fasting insulin, HbA1c and Homeostasis Model Assessment Index of Insulin Resistance (HOMA–IR) were evaluated in the entire MESA cohort and in metabolic disease subgroups using linear regression models incrementally adjusted for age, gender, site, race, lifestyle, traditional risk factors and medications. Cross-sectional odds of prevalent impaired FBG, metabolic syndrome and Type 2 diabetes were calculated for GGT quintiles in the entire cohort and in subgroups defined by age (< or ≥65 years) and ethnicity.
Results
In multivariable models, significant associations were present between GGT activity and FBG, fasting insulin, HbA1c and HOMA–IR, with the interaction between GGT and BMI affecting the association between GGT and HOMA–IR as well as the association between BMI and HOMA–IR (p < 0.0001). Adjusted odds ratios (95% CIs) of prevalent impaired FBG, metabolic syndrome and Type 2 diabetes for quintile 5 versus 1 in the entire cohort were 2.4 (1.7–3.5), 3.3 (2.5–4.5) and 2.8 (1.8–4.4), respectively (p < 0.0001). GGT associations weakened with age. The significance of linear trends for increased prevalent metabolic disease by increasing GGT quintile varied by ethnicity.
Conclusion
GGT is strongly associated with both cardiovascular and metabolic risk factors, including prevalent metabolic disease, in the MESA cohort.
doi:10.2217/bmm.13.71
PMCID: PMC4106917  PMID: 24044563
γ-glutamyltransferase; GGT; glutathione; metabolic syndrome; oxidative stress; Type 2 diabetes
21.  Ethnicity and Sex Modify the Association of Serum C-Reactive Protein with Microalbuminuria 
Ethnicity & disease  2008;18(3):324-329.
Objectives
To study the association between serum C-reactive protein (CRP) and urinary albumin excretion in the Multi-Ethnic Study of Atherosclerosis and to assess whether the association is modified by ethnicity, sex, or systolic blood pressure.
Methods
This was a cross-sectional study of 6675 participants who were free from macro albuminuria and clinical cardiovascular disease (mean age 62.1 years, 53% female; 39% White, 27% African American, 22% Hispanic, and 12% Chinese). Urinary albumin excretion was measured by spot urine albumin-to-creatinine ratio (ACR). Effect modifications were tested after adjusting for age, diabetes, body mass index, smoking, use of angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker, other antihypertensive drugs, estrogens, statins, and high-density lipoprotein cholesterol and triglyceride levels.
Results
The association between CRP and ACR was modified by ethnicity (P=.01) and sex (P<.001), but not by systolic blood pressure. After multivariate adjustment, the association remained in Chinese, African American, and Hispanic men and African American women (P<.02 for African American men, and P<.04 for the other subgroups).
Conclusions
The association between CRP and ACR was modified by ethnicity and sex; it was stronger in non-White men and African American women. These interactions have not been reported before, and future studies should consider them.
PMCID: PMC4089959  PMID: 18785447
Albuminuria; C-Reactive Protein; Ethnicity; Gender
22.  Regulatory Decisions on Endocrine Disrupting Chemicals Should be Based on the Principles of Endocrinology 
For years, scientists from various disciplines have studied the effects of endocrine disrupting chemicals (EDCs) on the health and wellbeing of humans and wildlife. Some studies have specifically focused on the effects of low doses, i.e. those in the range that are thought to be safe for humans and/or animals. Others have focused on the existence of non-monotonic dose-response curves. These concepts challenge the way that chemical risk assessment is performed for EDCs. Continued discussions have clarified exactly what controversies and challenges remain. We address several of these issues, including why the study and regulation of EDCs should incorporate endocrine principles; what level of consensus there is for low dose effects; challenges to our understanding of non-monotonicity; and whether EDCs have been demonstrated to produce adverse effects. This discussion should result in a better understanding of these issues, and allow for additional dialogue on their impact on risk assessment.
doi:10.1016/j.reprotox.2013.02.002
PMCID: PMC3902067  PMID: 23411111
weight of evidence; organizational; adaptive effect; hormesis; human exposure; epidemiology; flare
23.  Hostility Modifies the Association between TV Viewing and Cardiometabolic Risk 
Journal of Obesity  2014;2014:784594.
Background. It was hypothesized that television viewing is predictive of cardiometabolic risk. Moreover, people with hostile personality type may be more susceptible to TV-induced negative emotions and harmful health habits which increase occurrence of cardiometabolic risk. Purpose. The prospective association of TV viewing on cardiometabolic risk was examined along with whether hostile personality trait was a modifier. Methods. A total of 3,269 Black and White participants in the coronary artery risk development in young adults (CARDIA) study were assessed from age 23 to age 35. A cross-lagged panel model at exam years 5, 10, 15, and 20, covering 15 years, was used to test whether hours of daily TV viewing predicted cardiometabolic risk, controlling confounding variables. Multiple group analysis of additional cross-lagged panel models stratified by high and low levels of hostility was used to evaluate whether the association was modified by the hostile personality trait. Results. The cross-lagged association of TV viewing at years 5 and 15 on clustered cardiometabolic risk score at years 10 and 20 was significant (B = 0.058 and 0.051), but not at 10 to 15 years. This association was significant for those with high hostility (B = 0.068 for exam years 5 to 10 and 0.057 for exam years 15 to 20) but not low hostility. Conclusion. These findings indicate that TV viewing is positively associated with cardiometabolic risk. Further, they indicate that hostility might be a modifier for the association between TV viewing and cardiometabolic risk.
doi:10.1155/2014/784594
PMCID: PMC4094870  PMID: 25050178
24.  Arterial Wave Reflections and Incident Cardiovascular Events and Heart Failure: The Multiethnic Study of Atherosclerosis 
Background
Experimental and physiologic data mechanistically implicate wave reflections in the pathogenesis of left ventricular failure and cardiovascular disease, but their association with these outcomes in the general population is unclear.
Objectives
To assess the relationship between central pressure profiles and incident cardiovascular events.
Methods
Aortic pressure waveforms were derived from a generalized transfer function applied to the radial pressure waveform recorded non-invasively from 5,960 participants in the Multiethnic Study of Atherosclerosis (MESA). The central pressure waveform was separated into forward and reflected waves using a physiologic flow waveform. Reflection magnitude (RM=[reflected/forward wave amplitude] ×100), augmentation index (AIx=[second/first systolic peak] ×100) and pulse pressure amplification (PPA=[radial/aortic pulse pressure] ×100) were assessed as predictors of cardiovascular events (CVE) and congestive heart failure (CHF) during median 7.61 years of follow-up.
Results
After adjustment for established risk factors, aortic AIx independently predicted hard CVE (HR per 10%-increase=1.08; 95%CI=1.01-1.14; P=0.016), whereas PPA independently predicted all CVE (HR per 10%-increase=0.82; 95%CI=0.70-0.96; P=0.012). RM was independently predictive of all CVE (hazard ratio [HR] per 10%-increase=1.34; 95%CI=1.08-1.67; P=0.009), hard CVE (HR per 10%-increase=1.46; 95%CI=1.12-1.90; P=0.006) and strongly predictive of new-onset CHF (HR per 10%-increase=2.69; 95%CI=1.79-4.04; P<0.0001), comparing favorably to other risk factors for CHF as judged by various measures of model performance, reclassification and discrimination. In a fully-adjusted model, compared to non-hypertensive subjects with low RM, the HR for hypertensive subjects with low RM, non-hypertensive subjects with high RM and hypertensive subjects with high RM were 1.81 (95%CI=0.85-3.86), 2.16 (95%CI=1.07-5.01) and 3.98 (95%CI=1.96-8.05), respectively.
Conclusions
Arterial wave reflections represent a novel strong risk factor for CHF in the general population.
doi:10.1016/j.jacc.2012.07.054
PMCID: PMC4065497  PMID: 23103044
wave reflections; cardiovascular risk; heart failure. arterial hemodynamics; left ventricular afterload
25.  Adult-Onset Asthma Becomes the Dominant Phenotype among Women by Age 40 Years. The Longitudinal CARDIA Study 
Rationale: Although asthma is usually considered to originate in childhood, adult-onset disease is being increasingly reported.
Objectives: To contrast the proportion and natural history of adult-onset versus pediatric-onset asthma in a community-based cohort. We hypothesized that asthma in women is predominantly of adult onset rather than of pediatric onset.
Methods: This study used data from the Coronary Artery Risk Development in Young Adults (CARDIA) cohort in the United States over a 25-year period. Adult- and pediatric-onset asthma phenotypes were studied, as defined by age at onset of 18 years or older. Subjects with asthma were categorized by sex, obesity, atopy, smoking, and race by mean age/examination year, using a three-way analysis of covariance model. Natural history of disease was examined using probabilities derived from a Markov chain model.
Measurements and Main Results: Asthma of adult onset became the dominant (i.e., exceeded 50%) phenotype in women by age 40 years. The age by which adult-onset asthma became the dominant phenotype was further lowered for obese, nonatopic, ever-smoking, or white women. The prevalence trend with increasing time for adult-onset disease was greater among subjects with nonatopic than atopic asthma among both sexes. Furthermore, adult-onset asthma had remarkable sex-related differences in risk factors. In both sexes, the quiescent state for adult-onset asthma was less frequent and also “less stable” over time than for pediatric-onset asthma.
Conclusions: Using a large national cohort, this study challenges the dictum that most asthma in adults originates in childhood. Studies of the differences between pediatric- and adult-onset asthma may provide greater insight into the phenotypic heterogeneity of asthma.
doi:10.1513/AnnalsATS.201212-115OC
PMCID: PMC3960903  PMID: 23802814
adult-onset; pediatric-onset; obesity; nonatopic; recrudescent

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