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1.  Association of N-Linked Glycoprotein Acetyls and Colorectal Cancer Incidence and Mortality 
PLoS ONE  2016;11(11):e0165615.
Acute phase proteins highlight the dynamic interaction between inflammation and oncogenesis. GlycA, a novel nuclear magnetic resonance (NMR) inflammatory marker that identifies primarily circulating N-acetyl glycan groups attached to acute phase proteins, may be a future CRC risk biomarker.
We examined the association between GlycA and incident CRC and mortality in two prospective cohorts (N = 34,320); Discovery cohort: 27,495 participants from Women's Health Study (WHS); Replication cohort: 6,784 participants from Multi-Ethnic Study of Atherosclerosis (MESA). Multivariable Cox models were adjusted for clinical risk factors and compared GlycA to acute phase proteins (high-sensitivity C-reactive protein [hsCRP], fibrinogen, and soluble intercellular adhesion molecule-1 [sICAM-1]).
In WHS (median follow-up 19 years, 337 cases, 103 deaths), adjusted HRs (95% CIs) per SD increment of GlycA for CRC incidence and mortality were 1.19 (1.06–1.35; p = 0.004) and 1.24 (1.00–1.55; p = 0.05), respectively. We replicated findings in MESA (median follow-up 11 years, 70 cases, 23 deaths); HRs (95% CIs) per SD of GlycA for CRC incidence and mortality were 1.32 (1.06–1.65; p = 0.01) and 1.54 (1.06–2.23; p = 0.02), respectively, adjusting for age, sex, and race. Pooled analysis, adjusted HR (95% CI) per SD of GlycA for CRC incidence and mortality was 1.26 (1.15–1.39; p = 1 x 10−6). Other acute phase proteins (hsCRP, fibrinogen, and sICAM-1) had weaker or no association with CRC incidence, while only fibrinogen and GlycA were associated with CRC mortality.
The clinical utility of GlycA to personalize CRC therapies or prevention warrants further study.
Trial Registration WHS NCT00000479, MESA NCT00005487
PMCID: PMC5130185  PMID: 27902713
2.  Duration and Degree of Weight Gain and Incident Diabetes in Younger Versus Middle-Aged Black and White Adults: ARIC, CARDIA, and the Framingham Heart Study 
Diabetes Care  2015;38(11):2042-2049.
To determine whether duration and degree of weight gain are differentially associated with diabetes risk in younger versus middle-aged black and white adults.
We combined data from three cohort studies: Atherosclerosis Risk in Communities (ARIC), Coronary Artery Risk Development in Young Adults (CARDIA), and the Framingham Heart Study. A total of 17,404 participants (56% women; 21% black) were stratified by baseline age (younger: ≥30 and <45 years; middle-aged: ≥45 and <60 years) and examined for incident diabetes (median follow-up 9 years). Duration and degree of gain in BMI were calculated as “BMI-years” above one’s baseline BMI.
Diabetes incidence per 1,000 person-years in the younger and middle-aged groups was 7.2 (95% CI 5.7, 8.7) and 24.4 (22.0, 26.8) in blacks, respectively, and 3.4 (2.8, 4.0) and 10.5 (9.9, 11.2) in whites, respectively. After adjusting for sex, baseline BMI and other cardiometabolic factors, and age and race interaction terms, gains in BMI-years were associated with higher risk of diabetes in the younger compared with middle-aged groups: hazard ratios for 1-unit increase in log BMI-years in younger versus middle-aged blacks were 1.18 (P = 0.02) and 1.02 (P = 0.39), respectively (P for interaction by age-group = 0.047), and in whites were 1.35 (P < 0.001) and 1.11 (P < 0.001), respectively (P for interaction by age-group = 0.008).
Although middle-aged adults have higher rates of diabetes, younger adults are at greater relative risk of developing diabetes for a given level of duration and degree of weight gain.
PMCID: PMC4613922  PMID: 26358286
3.  Association of Fitness With Incident Dyslipidemias Over 25 Years in the Coronary Artery Risk Development in Young Adults Study 
Few studies have examined the longitudinal associations of fitness or changes in fitness on the risk of developing dyslipidemias. This study examined the associations of: (1) baseline fitness with 25-year dyslipidemia incidence; and (2) 20-year fitness change on dyslipidemia development in middle age in the Coronary Artery Risk Development in young Adults (CARDIA) study.
Multivariable Cox proportional hazards regression models were used to test the association of baseline fitness (1985–1986) with dyslipidemia incidence over 25 years (2010–2011) in CARDIA (N=4,898). Modified Poisson regression models were used to examine the association of 20-year change in fitness with dyslipidemia incidence between Years 20 and 25 (n=2,487). Data were analyzed in June 2014 and February 2015.
In adjusted models, the risk of incident low high-density lipoprotein cholesterol (HDL-C), high triglycerides, and high low-density lipoprotein cholesterol (LDL-C) was significantly lower, by 9%, 16%, and 14%, respectively, for each 2.0-minute increase in baseline treadmill endurance. After additional adjustment for baseline trait level, the associations remained significant for incident high triglycerides and high LDL-C in the total population and for incident high triglycerides in both men and women. In race-stratified models, these associations appeared to be limited to whites. In adjusted models, change in fitness did not predict 5-year incidence of dyslipidemias, whereas baseline fitness significantly predicted 5-year incidence of high triglycerides.
Our findings demonstrate the importance of cardiorespiratory fitness in young adulthood as a risk factor for developing dyslipidemias, particularly high triglycerides, during the transition to middle age.
PMCID: PMC4615297  PMID: 26165197
4.  Relation of Cardiometabolic Risk Factors Between Parents and Children 
The Journal of pediatrics  2015;167(5):1049-1056.e2.
To explore the relations of parent-child cardiometabolic risk factors and assess the influence of adiposity on these associations.
Study design
Associations of adiposity, blood pressure, lipids, fasting insulin and glucose, and a risk factor cluster score were evaluated in a cross-sectional study of 179 parents and their children (6–18 years, N=255). Insulin resistance was assessed by euglycemic clamp in parents and children aged 10 or older. Metabolic syndrome in parents was defined by ATPIII criteria. Cluster scores of the risk factors were created based on age-specific z-scores. Analyses included Pearson correlation and linear regression, adjusted for parent and child age, sex, race, and body mass index (BMI), accounting for within-family correlation.
We found positive parent-child correlations for measures of adiposity (BMI, BMI percentile, waist, subcutaneous fat, and visceral fat; r=0.22–0.34, all p≤0.003), systolic blood pressure (SBP) (r=0.20, p=0.002), total cholesterol (r=0.39, p<0.001), low-density lipoprotein cholesterol (r=0.34, p<0.001), high density lipoprotein cholesterol (r=0.26, p<0.001) triglycerides (r=0.19, p=0.01) and insulin sensitivity (r=0.22, p=0.02) as well as cluster scores (r=0.15, p=0.02). After adjustment for BMI all parent-child correlations, except systolic blood pressure, remained significant.
Although adiposity is strongly correlated between parents and children, many cardiometabolic risk factors correlate independent of parent and child BMI. Adverse parental cardiometabolic profiles may identify at-risk children independent of the child’s adiposity status.
PMCID: PMC4661075  PMID: 26307644
adiposity; obesity; blood pressure; BMI; cardiovascular; cluster score; correlation; insulin sensitivity; lipid(s)
5.  Nocturnal Blood Pressure in Young Adults and Cognitive Function in Midlife: The Coronary Artery Risk Development in Young Adults (CARDIA) Study 
American Journal of Hypertension  2015;28(10):1240-1247.
Nocturnal blood pressure (BP) is associated with risk for cardiovascular events. However, the relationship between nocturnal BP in young adults and cognitive function in midlife remains unclear.
We used data from the ambulatory BP monitoring substudy of the Coronary Artery Risk Development in Young Adults Study, including 224 participants (mean age 30 years, 45% men, 63% African Americans). At the 20-year follow-up, the Stroop test (executive function), Digit Symbol Substitution Test (psychomotor speed), and Rey Auditory Verbal Learning Test (verbal memory) were assessed.
Baseline mean office, daytime, and nocturnal BP were 109/73, 120/74, and 107/59mm Hg, respectively. Nocturnal BP dipping, calculated as (nocturnal systolic BP [SBP] − daytime SBP) × 100/daytime SBP, was divided into quartiles (Q1: −39.3% to −16.9%; Q2: −16.8% to −13.2%, Q3 [reference]: −13.1% to −7.8%, and Q4: −7.7% to +56.4%). In multiple regression analyses, the least nocturnal SBP dipping (Q4 vs. reference) and higher nocturnal diastolic BP level were associated with worse Stroop scores, with adjustments for demographic and clinical characteristics, and cumulative exposure to office BP during follow-up (β [standard error]: 0.37 [0.18] and 0.19 [0.07], respectively; all P < 0.05). Digit Symbol Substitution Test and Rey Auditory Verbal Learning Test were not significantly associated with nocturnal SBP dipping or nocturnal SBP/diastolic BP levels.
Among healthy young adults, less nocturnal SBP dipping and higher nocturnal diastolic BP levels were associated with lower executive function in midlife, independent of multiple measures of office BP during long-term follow-up.
PMCID: PMC4580541  PMID: 25783740
blood pressure; cognitive function; hypertension; midlife;  nocturnal blood pressure; young adults.
6.  Alterations of a Cellular Cholesterol Metabolism Network Are a Molecular Feature of Obesity-Related Type 2 Diabetes and Cardiovascular Disease 
Diabetes  2015;64(10):3464-3474.
Obesity is linked to type 2 diabetes (T2D) and cardiovascular diseases; however, the underlying molecular mechanisms remain unclear. We aimed to identify obesity-associated molecular features that may contribute to obesity-related diseases. Using circulating monocytes from 1,264 Multi-Ethnic Study of Atherosclerosis (MESA) participants, we quantified the transcriptome and epigenome. We discovered that alterations in a network of coexpressed cholesterol metabolism genes are a signature feature of obesity and inflammatory stress. This network included 11 BMI-associated genes related to sterol uptake (↑LDLR, ↓MYLIP), synthesis (↑SCD, FADS1, HMGCS1, FDFT1, SQLE, CYP51A1, SC4MOL), and efflux (↓ABCA1, ABCG1), producing a molecular profile expected to increase intracellular cholesterol. Importantly, these alterations were associated with T2D and coronary artery calcium (CAC), independent from cardiometabolic factors, including serum lipid profiles. This network mediated the associations between obesity and T2D/CAC. Several genes in the network harbored C-phosphorus-G dinucleotides (e.g., ABCG1/cg06500161), which overlapped Encyclopedia of DNA Elements (ENCODE)-annotated regulatory regions and had methylation profiles that mediated the associations between BMI/inflammation and expression of their cognate genes. Taken together with several lines of previous experimental evidence, these data suggest that alterations of the cholesterol metabolism gene network represent a molecular link between obesity/inflammation and T2D/CAC.
PMCID: PMC4587646  PMID: 26153245
7.  DNA Methylation of the Aryl Hydrocarbon Receptor Repressor Associations with Cigarette Smoking and Subclinical Atherosclerosis 
Tobacco smoke contains numerous agonists of the aryl-hydrocarbon receptor (AhR) pathway, and activation of the AhR pathway was shown to promote atherosclerosis in mice. Intriguingly, cigarette smoking is most strongly and robustly associated with DNA modifications to an AhR pathway gene, the aryl-hydrocarbon receptor repressor (AHRR). We hypothesized that altered AHRR methylation in monocytes, a cell type sensitive to cigarette smoking and involved in atherogenesis, may be a part of the biological link between cigarette smoking and atherosclerosis.
Methods and Results
DNA methylation profiles of AHRR in monocytes (542 CpG sites ± 150kb of AHRR, using Illumina 450K array) were integrated with smoking habits and ultrasound-measured carotid plaque scores from 1,256 participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Methylation of cg05575921 significantly associated (p = 6.1×10−134) with smoking status (current vs. never). Novel associations between cg05575921 methylation and carotid plaque scores (p = 3.1×10−10) were identified, which remained significant in current and former smokers even after adjusting for self-reported smoking habits, urinary cotinine, and well-known CVD risk factors. This association replicated in an independent cohort using hepatic DNA (n = 141). Functionally, cg05575921 was located in a predicted gene expression regulatory element (enhancer), and had methylation correlated with AHRR mRNA profiles (p = 1.4×10−17) obtained from RNA sequencing conducted on a subset (n = 373) of the samples.
These findings suggest AHRR methylation may be functionally related to AHRR expression in monocytes, and represents a potential biomarker of subclinical atherosclerosis in smokers.
PMCID: PMC4618776  PMID: 26307030
smoking; atherosclerosis; gene expression/regulation; epidemiology; epigenetics; DNA methylation
8.  Microbiota‐Dependent Metabolite Trimethylamine N‐Oxide and Coronary Artery Calcium in the Coronary Artery Risk Development in Young Adults Study (CARDIA) 
Clinical studies implicate trimethylamine N‐oxide (TMAO; a gut microbiota‐dependent nutrient metabolite) in cardiovascular disease risk. There is a lack of population‐based data on the role of TMAO in advancing early atherosclerotic disease. We tested the prospective associations between TMAO and coronary artery calcium (CAC) and carotid intima‐media thickness (cIMT).
Methods and Results
Data were from the Coronary Artery Risk Development in Young Adults Study (CARDIA), a biracial cohort of US adults recruited in 1985–1986 (n=5115). We randomly sampled 817 participants (aged 33–55 years) who attended examinations in 2000–2001, 2005–2006, and 2010–2011, at which CAC was measured by computed tomography and cIMT (2005–2006) by ultrasound. TMAO was quantified using liquid chromotography mass spectrometry on plasma collected in 2000–2001. Outcomes were incident CAC, defined as Agatston units=0 in 2000–2001 and >0 over 10‐year follow‐up, CAC progression (any increase over 10‐year follow‐up), and continuous cIMT. Over the study period, 25% (n=184) of those free of CAC in 2000–2001 (n=746) developed detectable CAC. In 2000–2001, median (interquartile range) TMAO was 2.6 (1.8–4.2) μmol/L. In multivariable‐adjusted models, TMAO was not associated with 10‐year CAC incidence (rate ratio=1.03; 95% CI: 0.71–1.52) or CAC progression (0.97; 0.68–1.38) in Poisson regression, or cIMT (beta coefficient: −0.009; −0.03 to 0.01) in linear regression, comparing the fourth to the first quartiles of TMAO.
In this population‐based study, TMAO was not associated with measures of atherosclerosis: CAC incidence, CAC progression, or cIMT. These data indicate that TMAO may not contribute significantly to advancing early atherosclerotic disease risk among healthy early‐middle‐aged adults.
PMCID: PMC5121500  PMID: 27792658
atherosclerosis; biomarker; epidemiology; follow‐up study; risk factor; Epidemiology; Risk Factors; Computerized Tomography (CT); Atherosclerosis; Biomarkers
9.  Variants in the Adiponectin Gene and Serum Adiponectin: The Coronary Artery Development in Young Adults (CARDIA) Study 
Obesity (Silver Spring, Md.)  2010;18(12):2333-2338.
Circulating adiponectin is involved in the atherosclerotic process and has been associated with cardiovascular disease as well as obesity, insulin resistance, metabolic syndrome, and type 2 diabetes. The adiponectin gene (ADIPOQ) encodes the circulating protein adiponectin and affects its expression. Only a small proportion of all known ADIPOQ polymorphisms have been investigated in relation to circulating adiponectin concentrations. Using data from 3,355 African-American and white men and women aged 33–45 at the year 15 examination from the Coronary Artery Development in Young Adults (CARDIA) Study the association between 10 single-nucleotide polymorphisms (SNPs) within ADIPOQ and serum adiponectin was examined using linear regression. SNPs were chosen based on a tagSNP approach. Models were stratified by self-reported race to control for population stratification, and Bonferroni corrected for multiple comparisons. ADIPOQ SNPs rs17300539 (P < 0.0001), rs182052 (P = 0.0013), rs822393 (P = 0.0005), rs9882205 (P = 0.0001), and rs3774261 (P = 0.0001) were strongly associated with serum adiponectin concentrations in whites. In general, there was a dose–response relationship of adjusted mean adiponectin concentrations across genotypes. Only one SNP, rs17300539 was marginally associated with serum adiponectin concentrations (P = 0.0087) in African Americans. Significant interactions were found between waist and rs182052 (P = 0.0029) and between rs9882505 and smoking (P = 0.001) in whites. Many ADIPOQ SNPs have not yet been examined, and additional studies are needed to determine whether these may be functional variants.
PMCID: PMC4970734  PMID: 20395949
10.  Age at menarche and cardiometabolic risk in adulthood: the Coronary Artery Risk Development in Young Adults Study 
The Journal of pediatrics  2015;167(2):344-352.e1.
To examine the association of menarche timing with cardiometabolic risk factors into early to mid-adulthood, comparing African-American and White women.
Study design
Analyses included 2,583 women (African-American=1,333; White=1,250) from the Coronary Artery Risk Development in Young Adults (CARDIA) cohort study over 25 years of follow-up (1985–2011). Outcomes included type 2 diabetes, metabolic syndrome, adiposity, glucose, insulin, blood pressure, and blood lipids. Cox models or repeated measures linear regression models estimated the association between age at menarche and the outcomes.
Each one-year earlier age at menarche was associated with higher mean BMI among African-American (0.88±0.12 kg/m2, p<.0001) and White (0.89±0.10 kg/m2, p<.0001) women. After BMI adjustment, each one-year earlier age at menarche was associated with higher triglycerides (2.26±0.68 mg/dl, p=0.001) and glucose (0.34±0.11 mg/dl, p=0.002), and greater risk for incident impaired fasting glucose (HR=1.13 95% CI 1.04–1.20) and metabolic syndrome (HR=1.19, 95% CI 1.11–1.26) among white women only.
Excess adiposity associated with earlier menarche is sustained through mid-adulthood, and primarily drives higher cardiometabolic risk factor levels. However, White women with earlier menarche had increased risk of a number of insulin-resistance related conditions independent of adiposity. The cardiometabolic impact of earlier menarche was weaker in African-American women despite higher average adiposity. Weight maintenance would likely reduce, but may not completely eliminate the elevated cardiometabolic risk of earlier menarche.
PMCID: PMC4516565  PMID: 25962931
Epidemiology; Menarche; Puberty; Type 2 diabetes; Metabolic Syndrome; Obesity
11.  Intima Media Thickness and Cognitive Function in Stroke-Free Middle-Aged Adults: Findings from the CARDIA study 
Background and Purpose
The relationship between carotid artery intima media thickness (IMT) and cognitive function in midlife remains relatively unexplored. We examined the association between IMT and cognitive function in a middle-aged epidemiologic cohort of 2,747 stroke-free participants.
At the Year 20 visit (our study baseline), participants from the Coronary Artery Risk Development in Young Adults study had IMT measured by ultrasound at the common carotid artery. Five years later, participants completed a cognitive battery consisting of the Rey Auditory-Verbal Learning Test of verbal memory, the Digit Symbol Substitution Test of processing speed, and the Stroop test of executive function. We transformed cognitive scores into standardized z-scores, with negative values indicating worse performance.
Mean age at baseline was 45.3 years (SD=3.6). Greater IMT (per 1SD difference of 0.12mm) was significantly associated with worse performance on all cognitive tests (z-scores) in unadjusted linear regression models (Verbal Memory=−0.16, 95%CI=−0.20 to −0.13; Processing Speed=−0.23, 95%CI=−0.27 to −0.19; and Executive Function=−0.17, 95%CI= −0.20 to −0.13). In models adjusted for socio-demographics and vascular risk factors that lie earlier in the causal pathway, greater IMT remained negatively associated with processing speed (−0.06,95%CI=−0.09 to −0.02; p=0.003) and borderline associated with executive function (−0.03, 95%CI=−0.07 to 0.00; p=0.07) but not with verbal memory.
We observed an association between greater IMT and worse processing speed – a key component of cognitive functioning- at middle-age above and beyond traditional vascular risk factors. Efforts targeted at preventing early stages of atherosclerosis may modify the course of cognitive aging.
PMCID: PMC4519386  PMID: 26106116
Cognition; Epidemiology; Intima Media Thickness; Risk Factors; Stroke-Free
12.  What an anti-cardiovascular diet should be in 2015 
Current opinion in lipidology  2015;26(4):270-275.
Purpose of review
Given scientific and public debate about optimal diet to prevent cardiovascular disease, and interest in diet and other chronic diseases, we propose that following a few simple dietary principles would reduce chronic disease incidence.
Recent findings
Nutrition research has been criticized for focusing on individual nutrients and foods, treated like drug therapy. With a few important exceptions, clinical trials of supplemental nutrients have not shown benefit. Although highly specific nutrition information is elusive, diet patterns have provided consistent answers, important for public health. Observational cohort studies have found that some dietary patterns are reported with high reliability over long periods and predict future cardiovascular and other inflammatory-related diseases. Two randomized clinical trials confirmed this finding. There are many common features of Mediterranean and prudent diets, particularly the plant-centered aspect, coupled with variety of foods eaten. A dietary pattern characterized by high fruit, vegetable, legume, whole grain, nut, berry, seed, and fish intakes, and possibly to intakes of dairy, coffee, tea, chocolate, and alcohol (not in excess), but low meat and detrimentally processed foods is associated with reduced incidence of cardiovascular disease and rates of non-cardiovascular, non-cancer chronic inflammatory-related mortality.
A plant-centered diet may be broadly recommended.
PMCID: PMC4557621  PMID: 26103605
chronic disease; cardiovascular disease; diet patterns; plant-centered diet
13.  Coronary Artery Calcium Score and Association with Recurrent Nephrolithiasis: The Multi-Ethnic Study of Atherosclerosis 
The Journal of urology  2015;195(4 Pt 1):971-976.
Subclinical coronary artery calcification is an established predictor of cardiovascular events. While a history of kidney stones has been linked to subclinical carotid atherosclerosis, to our knowledge no study has examined its relationship with coronary artery calcification. We studied the association between kidney stone history and prevalent coronary artery calcification in MESA (Multi-Ethnic Study of Atherosclerosis).
Materials and Methods
MESA is a multisite cohort study of participants 45 to 84 years old without known cardiovascular disease at baseline from 2000 to 2002. Computerized tomography was done in 3,282 participants at followup in 2010 to 2012 to determine coronary artery calcification and kidney stone history was assessed by self-report. Coronary artery calcification scores were categorized as none—0, mild—1 to 99, moderate—100 to 399 or severe—400 or greater. Cross-sectional analysis was performed adjusting for demographic and dietary factors related to kidney stones.
The prevalence of kidney stone disease history was approximately 9%, mean ± SD participant age was 69.5 ± 9.3 years, 39% of participants were Caucasian, 47% were men and 69% had detectable coronary artery calcification (score greater than 0). No difference in the score was seen between single stone formers and nonstone formers. Recurrent kidney stone formation was associated with moderate or severe calcification on multivariable logistic regression vs none or mild calcification (OR 1.80, 95% CI 1.22–2.67). When coronary artery calcification scores were separated into none, mild, moderate and severe calcification, recurrent stone formation was associated with a higher score category on multivariable ordinal logistic regression (OR 1.44 per category, 95% CI 1.04–2.01).
Recurrent kidney stone formation is associated with subclinical coronary atherosclerosis. This association appeared stronger with coronary artery calcification severity than with coronary artery calcification presence.
PMCID: PMC4966606  PMID: 26454103
kidney; urolithiasis; coronary artery disease; arteriosclerosis; recurrence
14.  Vascular risk factors, cerebrovascular reactivity, and the default-mode brain network 
NeuroImage  2015;115:7-16.
Cumulating evidence from epidemiologic studies implicates cardiovascular health and cerebrovascular function in several brain diseases in late life. We examined vascular risk factors with respect to a cerebrovascular measure of brain functioning in subjects in mid-life, which could represent a marker of brain changes in later life. Breath-hold functional MRI (fMRI) was performed in 541 women and men (mean age 50.4 years) from the Coronary Artery Risk Development in Young Adults (CARDIA) Brain MRI sub-study. Cerebrovascular reactivity (CVR) was quantified as percentage change in blood-oxygen level dependent (BOLD) signal in activated voxels, which was mapped to a common brain template and log-transformed. Mean CVR was calculated for anatomic regions underlying the default-mode network (DMN) - a network implicated in AD and other brain disorders - in addition to areas considered to be relatively spared in the disease (e.g. occipital lobe), which were utilized as reference regions. Mean CVR was significantly reduced in the posterior cingulate/precuneus (β = -0.063, 95% CI: - 0.106, -0.020), anterior cingulate (β = -0.055, 95% CI: -0.101, -0.010), and medial frontal lobe (β = -0.050, 95% CI: -0.092, -0.008) relative to mean CVR in the occipital lobe, after adjustment for age, sex, race, education, and smoking status, in subjects with pre-hypertension/hypertension compared to normotensive subjects. By contrast, mean CVR was lower, but not significantly, in the inferior parietal lobe (β = -0.024, 95% CI: -0.062, 0.014) and the hippocampus (β = -0.006, 95% CI: -0.062, 0.050) relative to mean CVR in the occipital lobe. Similar results were observed in subjects with diabetes and dyslipidemia compared to those without these conditions, though the differences were non-significant. Reduced CVR may represent diminished vascular functionality for the DMN for individuals with prehypertension/ hypertension in mid-life, and may serve as a preclinical marker for brain dysfunction in later life.
PMCID: PMC4469180  PMID: 25917517
Alzheimer's disease; neurophysiology; vascular risk factors
15.  Oxidative stress, inflammation, endothelial dysfunction and incidence of type 2 diabetes 
Oxidative stress, inflammation and endothelial dysfunction are interrelated factors in the etiology of cardiovascular disease, but their linkage to type 2 diabetes is less clear. We examined the association of these biomarkers with incident type 2 diabetes (T2D).
Analysis of 2339 participants in the community-based coronary artery risk development in young adults (CARDIA) study. Participants (age 40.1 ± 3.6 years, 44 % Black, 58 % women) were free of diabetes, and were followed 10 years. Cox regression was used to estimate hazard ratios (HRs) for incident T2D adjusting for the other biomarkers under study, demographic and lifestyle measures, dietary biomarkers, BMI (kg/m2) and metabolic syndrome components.
F2-isoprostanes and oxidized LDL (oxidative stress) were positively associated with incident T2D, but the associations were attenuated by adjustment for BMI. C-reactive protein was positively associated with T2D even with full adjustment: HR (95 % CI) = 2.21 (1.26–3.88) for quartile 4 (Q4) v. quartile 1 (Q1). The HR (95 % CI) for T2D for biomarkers of endothelial dysfunction ICAM-1 and E-selectin for Q4 v. Q1 were 1.64 (0.96–2.81) and 1.68 (1.04–2.71) respectively, with full adjustment. Including these two markers in a common risk score incorporating BMI and clinical measures improved the prediction probability of T2D: relative risk for the average person classified up compared to the average person classified down: 1.09, (1.06–1.13), P < 0.0001.
Biomarkers of inflammation and endothelial dysfunction were positively associated with incident T2D. ICAM-1 and E-selectin add to the prediction of T2D beyond a common risk score.
PMCID: PMC4806507  PMID: 27013319
Young adults; oxidative stress; Inflammation; Endothelial dysfunction; Incidence; Type 2 diabetes
16.  Loss of Lung Health from Young Adulthood and Cardiac Phenotypes in Middle Age 
Rationale: Chronic lung diseases are associated with cardiovascular disease. How these associations evolve from young adulthood forward is unknown. Understanding the preclinical history of these associations could inform prevention strategies for common heart-lung conditions.
Objectives: To use the Coronary Artery Risk Development in Young Adults (CARDIA) study to explore the development of heart-lung interactions.
Methods: We analyzed cardiac structural and functional measurements determined by echocardiography at Year 25 of CARDIA and measures of pulmonary function over 20 years in 3,000 participants.
Measurements and Main Results: Decline in FVC from peak was associated with larger left ventricular mass (β = 6.05 g per SD of FVC decline; P < 0.0001) and greater cardiac output (β = 0.109 L/min per SD of FVC decline; P = 0.001). Decline in FEV1/FVC ratio was associated with smaller left atrial internal dimension (β = −0.038 cm per SD FEV1/FVC decline; P < 0.0001) and lower cardiac output (β = −0.070 L/min per SD of FEV1/FVC decline; P = 0.03). Decline in FVC was associated with diastolic dysfunction (odds ratio, 3.39; 95% confidence interval, 1.37–8.36; P = 0.006).
Conclusions: Patterns of loss of lung health are associated with specific cardiovascular phenotypes in middle age. Decline in FEV1/FVC ratio is associated with underfilling of the left heart and low cardiac output. Decline in FVC with preserved FEV1/FVC ratio is associated with left ventricular hypertrophy and diastolic dysfunction. Cardiopulmonary interactions apparent with common complex heart and lung diseases evolve concurrently from early adulthood forward.
PMCID: PMC4511426  PMID: 25876160
lung; pulmonary heart disease; echocardiography; epidemiology
Hypertension  2015;66(1):23-29.
Aortic size increases with age, but factors related to such dilatation in healthy young adult population have not been studied. We aim to evaluate changes in aortic dimensions and its principal correlates among young adults over a 20-year time period. Reference values for aortic dimensions in young adults by echocardiography are also provided.
Healthy CARDIA study participants aged 23–35 years in 1990–91 (n=3051) were included after excluding 18 individuals with significant valvular dysfunction. Aortic root diameter by M-mode echocardiography at Year-5 (43.7% men; age 30.2±3.6y) and Year-25 CARDIA exams were obtained. Univariable and multivariable analyses were performed to assess associations of aortic root diameter with clinical data at Years-5 and -25. Aortic root diameter from Year-5 was used to establish reference values of aortic root diameter in healthy young adults.
Aortic root diameter at Year-25 was greater in men (33.3±3.7 vs 28.7±3.4mm, p<0.001) and in whites (30.9±4.3 vs 30.5±4.1, p=0.006). On multivariable analysis, aortic root diameter at Year-25 was positively correlated with male gender, white ethnicity, age, height, weight, 20-year gain in weight, active smoking at baseline and 20-year increase in diastolic, systolic and mean arterial pressure. A figure showing the estimated 95th percentile of aortic root diameter by age and body surface area stratified by race and gender is provided.
This study demonstrates that smoking, blood pressure, and increase in body weight are the main modifiable correlates of aortic root dilation during young adulthood. Our study also provides reference values for aortic root diameter in young adults.
PMCID: PMC4465858  PMID: 25941347
Ascending Aorta; Aortic Diseases; Aortic Aneurysm; Echocardiography; Epidemiology
18.  Twenty‐Five Year Secular Trends in Lipids and Modifiable Risk Factors in a Population‐Based Biracial Cohort: The Coronary Artery Risk Development in Young Adults (CARDIA) Study, 1985–2011 
Cross‐sectional analyses suggest that total and low‐density lipoprotein cholesterol (LDL‐c) trends that had been declining are now reversing. We examined longitudinal data from the Coronary Artery Risk Development in Young Adults (CARDIA) study to examine secular trends in total cholesterol, LDL‐c, high‐density lipoprotein cholesterol (HDL‐c), and triglycerides over 25 years. We also assessed whether modifiable lifestyle factors (body mass index, physical activity, alcohol consumption, smoking, and lipid‐lowering medications) are associated with these trends.
Methods and Results
CARDIA recruited 5115 black and white men and women ages 18 to 30 years from 4 US communities in 1985–1986, and re‐examined them 5, 10, 15, 20, and 25 years later. Secular trends, modeled as age‐matched time trends, were estimated using repeated‐measures regression stratified on race and sex. Total cholesterol and LDL‐c initially decreased ≈5 to 8 mg/dL between visits before plateauing and moving toward adverse trends in all groups, except black women, by year 25. HDL‐c showed an upward secular trend of 1 to 3 mg/dL between visits starting at year 15 in all groups; triglyceride trends were largely flat. Obesity and use of lipid‐lowering medications, which both increased over follow‐up, had strong independent, but opposite, associations with lipid trends over time. In aggregate, associations of modifiable lifestyle factors counterbalanced one another, minimally influencing secular trends.
Over 25 years, initially favorable trends in total cholesterol and LDL‐c have leveled off and may be reversing, persisting after control for modifiable risk factors. Factors such as dietary changes over 25 years and poor adherence to medications are candidates for additional investigation.
PMCID: PMC5015376  PMID: 27381757
epidemiology; lipids; population; risk factor; Epidemiology; Lipids and Cholesterol; Primary Prevention
19.  The association between N-terminal pro B-type natriuretic peptide and lipoprotein particle concentration plateaus at higher N-terminal pro B-type natriuretic peptide values: Multi-Ethnic Study on Atherosclerosis 
The association between N-terminal pro B-type natriuretic peptide (NT-proBNP) and blood levels of small and large LDL- and HDL- particle (P) concentration may not be linear throughout the whole range of NT-proBNP values.
Linear spline regression analysis between NT-proBNP and lipoprotein particle concentrations was performed cross-sectionally in 5597 individuals from the Multi-Ethnic Study of Atherosclerosis adjusted for age, race, sex, body mass index, % of energy from saturated fats, intentional exercise, statin use, antihypertensive medication use, diabetes, IL-6 and estimated glomerular filtration rate. Spline knots were selected as the point at which the linear slope changed in these associations.
NT-proBNP was positively associated with large LDL-P and HDL-P, but inversely associated with small LDL-P and HDL-P, but only for NT-proBNP values below the knot (range: 100–200 pg/mL).
These results suggest the presence of two distinct biological mechanisms above and below the knot determining the association between NT-proBNP and lipoprotein particle concentrations.
PMCID: PMC4782748  PMID: 25931335
NT-proBNP; Lipoprotein particles; MESA study; Nuclear magnetic resonance spectroscopy
20.  Ability of Reduced Lung Function to Predict Development of Atrial Fibrillation in Persons 45–84 Years of Age (From the Multi-Ethnic Study of Atherosclerosis-Lung Study) 
The American journal of cardiology  2015;115(12):1700-1704.
Atrial fibrillation (AF) occurs frequently in patients with chronic obstructive pulmonary disease (COPD). Epidemiological studies have found inconsistent associations between lung function and AF, and none have studied pulmonary emphysema, which overlaps only partially with COPD in the general population. In this study, we assessed the relationship between lung function measured by spirometry, the percent of emphysema-like lung on computed tomography and incident AF. The Multi-Ethnic Study of Atherosclerosis (MESA) study is a multicenter cohort study following 6814 subjects free of clinical cardiovascular disease including AF at baseline. Spirometry was performed in a subset of 3965 participants. Percent emphysema was defined on baseline CT scans as lung regions <950 hounsfield units. Incident AF was identified from hospital discharge diagnosis and Medicare claims data. Cox proportional hazards models were used to assess independent associations of lung volumes and percent emphysema with AF. 3811 participants with valid spirometry results were included in this study. The mean age was 64.5±9.8 years and 49.4% were men. AF developed in 149 individuals (3.8%) over a mean follow-up of 4.1 years after spirometry. Lower levels of forced expiratory volume at 1 second and forced vital capacity were associated with a higher risk of AF (HR 1.21 and 1.19 per 500ml respectively; p<0.001) after adjustment of demographic and cardiovascular risk factors. Percentage emphysema was not significantly related to AF. In conclusion, in a multi-ethnic community-based sample of individuals free of cardiovascular disease at baseline, functional airflow limitation was related to a higher risk of AF.
PMCID: PMC4450133  PMID: 25900353
Atrial Fibrillation; Lung function; Emphysema
21.  Cardiorespiratory fitness and brain volume and white matter integrity 
Neurology  2015;84(23):2347-2353.
We hypothesized that greater cardiorespiratory fitness is associated with lower odds of having unfavorable brain MRI findings.
We studied 565 healthy, middle-aged, black and white men and women in the CARDIA (Coronary Artery Risk Development in Young Adults) Study. The fitness measure was symptom-limited maximal treadmill test duration (Maxdur); brain MRI was measured 5 years later. Brain MRI measures were analyzed as means and as proportions below the 15th percentile (above the 85th percentile for white matter abnormal tissue volume).
Per 1-minute-higher Maxdur, the odds ratio for having less whole brain volume was 0.85 (p = 0.04) and for having low white matter integrity was 0.80 (p = 0.02), adjusted for age, race, sex, clinic, body mass index, smoking, alcohol, diet, physical activity, education, blood pressure, diabetes, total cholesterol, and lung function (plus intracranial volume for white matter integrity). No significant associations were observed between Maxdur and abnormal tissue volume or blood flow in white matter. Findings were similar for associations with continuous brain MRI measures.
Greater physical fitness was associated with more brain volume and greater white matter integrity measured 5 years later in middle-aged adults.
PMCID: PMC4464743  PMID: 25957331
22.  Association between inflammatory potential of diet and mortality in the Iowa Women’s Health study 
European journal of nutrition  2015;55(4):1491-1502.
Chronic diseases such as cancer and cardiovascular disease (CVD) are well-established causes of disability and premature deaths. Dietary components that are known to affect chronic inflammation have been implicated in the etiology and prognosis of these chronic diseases. We examined the ability of the dietary inflammatory index (DII) to predict overall, cancer and CVD mortality in the Iowa Women’s Health study.
The DII was computed from baseline dietary intake assessed in this cohort of 37,525 women, who were aged 55–69 years when enrolled starting in 1986. During the follow-up period, through December 31, 2010, in a total of 17,793 deaths, 5044 cancer- and 6528 CVD-related deaths were identified through mortality record linkage. Cox proportional hazards regression was used to estimate hazard ratios (HR) with DII expressed both as a continuous variable and as quartiles.
Comparing subjects in DII Quartile 4 versus Quartile 1, modest positive associations were noted for all-cause mortality (HRQ4vsQ1 1.07; 95 % CI 1.01–1.13; p-trend = 0.006), digestive cancer mortality (HRQ4vsQ1 1.19; 95 % CI 1.00–1.43; p-trend = 0.05), CVD mortality (HRQ4vsQ1 1.09; 95 % CI 1.01–1.18; p-trend = 0.08), non-cancer/non-CVD/non-acute mortality (HRQ4vsQ1 1.09; 95 % CI 1.00–1.19; p-trend = 0.19), coronary heart disease (CHD) mortality (HRQ4vsQ1 1.17; 95 % CI 1.05–1.30; p-trend = 0.001) and chronic obstructive pulmonary disease (COPD) mortality (HRQ4vsQ1 1.43; 95 % CI 1.18– 1.75; p-trend = 0.0006). No substantial associations were observed for mortality from stroke, Alzheimer’s disease or unspecified dementia.
These results indicate that a pro-inflammatory diet, as evidenced by higher DII scores, may be associated with total mortality as well as mortality from digestive cancer, CVD, CHD and COPD.
PMCID: PMC4892110  PMID: 26130324
Diet; Inflammation; Mortality; Cohort; Women
23.  Association of a 62 Variant Type 2 Diabetes Genetic Risk Score with Markers of Subclinical Atherosclerosis: A Transethnic, Multicenter Study 
Type 2 diabetes (T2D) and cardiovascular disease (CVD) share risk factors and subclinical atherosclerosis (SCA) predicts events in those with and without diabetes. T2D genetic risk may predict both T2D and SCA. We hypothesized that greater T2D genetic risk is associated with higher extent of SCA.
Methods and Results
In a cross-sectional analysis including up to 9,210 European Americans, 3,773 African Americans, 1,446 Hispanic Americans and 773 Chinese Americans without known CVD and enrolled in the FHS, CARDIA, MESA and GENOA studies, we tested a 62 T2D-loci genetic risk score (GRS62) for association with measures of SCA, including coronary artery (CACS) or abdominal aortic calcium score, common (CCA-IMT) and internal carotid artery intima-media thickness, and ankle-brachial index (ABI). We used ancestry-stratified linear regression models, with random effects accounting for family relatedness when appropriate, applying a genetic-only (adjusted for sex) and a full SCA risk factors adjusted model (significance = p<0.01 = 0.05/5, number of traits analyzed). An inverse association with CACS in MESA Europeans (fully-adjusted p=0.004) and with CCA-IMT in FHS (p=0.009) was not confirmed in other study cohorts, either separately or in meta-analysis. Secondary analyses showed no consistent associations with β-cell and insulin resistance sub-GRS in FHS and CARDIA.
SCA does not have a major genetic component linked to a burden of 62 T2D loci identified by large genome-wide association studies. A shared T2D-SCA genetic basis, if any, might become apparent from better functional information about both T2D and CVD risk loci.
PMCID: PMC4472563  PMID: 25805414
genetic association; risk assessment; subclinical atherosclerosis risk factor; type 2 diabetes mellitus; cardiovascular disease
24.  Gene-centric approach identifies new and known loci for FVIII activity and VWF antigen levels in European Americans and African Americans 
American journal of hematology  2015;90(6):534-540.
Coagulation factor VIII and von Willebrand factor (VWF) are key proteins in procoagulant activation. Higher FVIII coagulant activity (FVIII:C) and VWF antigen (VWF:Ag) are risk factors for cardiovascular disease and venous thromboembolism. Beyond associations with ABO blood group, genetic determinants of FVIII and VWF are not well understood, especially in non European-American populations. We performed a genetic association study of FVIII:C and VWF:Ag that assessed 50,000 gene-centric single nucleotide polymorphisms (SNPs) in 18,556 European Americans (EAs) and 5,047 African Americans (AAs) from five population-based cohorts. Previously unreported associations for FVIII:C were identified in both AAs and EAs with KNG1 (most significantly associated SNP rs710446, Ile581Thr, P=5.10 × 10−7 in EAs and P=3.88 × 10−3 in AAs) and VWF rs7962217 (Gly2705Arg, P=6.30 × 10−9 in EAs and P=2.98 × 10−2 in AAs). Significant associations for FVIII:C were also observed with F8/TMLHE region SNP rs12557310 in EAs (P=8.02 × 10−10), with VWF rs1800380 in AAs (P=5.62 × 10−11), and with MAT1A rs2236568 in AAs (P=1.69 × 10−6). We replicated previously reported associations of FVIII:C and VWF:Ag with the ABO blood group, VWF rs1063856 (Thr789Ala), rs216321 (Ala852Gln), and VWF rs2229446 (Arg2185Gln). Findings from this study expand our understanding of genetic influences for FVIII:C and VWF:Ag in both EAs and AAs.
PMCID: PMC4747096  PMID: 25779970
25.  Genome-wide association studies suggest sex-specific loci associated with abdominal and visceral fat 
To identify loci associated with abdominal fat and replicate prior findings, we performed genome-wide association (GWA) studies of abdominal fat traits: subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), total adipose tissue (TAT) and visceral to subcutaneous adipose tissue ratio (VSR).
Subjects and Methods
Sex-combined and sex-stratified analyses were performed on each trait with (TRAIT-BMI) or without (TRAIT) adjustment for BMI, and cohort-specific results were combined via a fixed effects meta-analysis. A total of 2,513 subjects of European descent were available for the discovery phase. For replication, 2,171 European Americans and 772 African Americans were available.
A total of 52 SNPs encompassing 7 loci showed suggestive evidence of association (p < 1.0 × 10−6) with abdominal fat in the sex-combined analyses. The strongest evidence was found on chromosome 7p14.3 between a SNP near BBS9 gene and VAT (rs12374818; p= 1.10 × 10−7), an association that was replicated (p = 0.02). For the BMI-adjusted trait, the strongest evidence of association was found between a SNP near CYCSP30 and VAT-BMI (rs10506943; p= 2.42 × 10−7). Our sex-specific analyses identified one genome-wide significant (p < 5.0 × 10−8) locus for SAT in women with 11 SNPs encompassing the MLLT10, DNAJC1 and EBLN1 genes on chromosome 10p12.31 (p = 3.97 × 10−8 to 1.13 × 10−8). The THNSL2 gene previously associated with VAT in women was also replicated (p= 0.006). The six gene/loci showing the strongest evidence of association with VAT or VAT-BMI were interrogated for their functional links with obesity and inflammation using the Biograph knowledge-mining software. Genes showing the closest functional links with obesity and inflammation were ADCY8 and KCNK9, respectively.
Our results provide evidence for new loci influencing abdominal visceral (BBS9, ADCY8, KCNK9) and subcutaneous (MLLT10/DNAJC1/EBLN1) fat, and confirmed a locus (THNSL2) previously reported to be associated with abdominal fat in women.
PMCID: PMC4821694  PMID: 26480920

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