Search tips
Search criteria

Results 1-25 (66)

Clipboard (0)

Select a Filter Below

more »
Year of Publication
Document Types
1.  Association Between Resting Heart Rate and Inflammatory Biomarkers (High-Sensitivity C-Reactive Protein, Interleukin-6, and Fibrinogen) (from the Multi-Ethnic Study of Atherosclerosis) 
The American journal of cardiology  2013;113(4):644-649.
Heart rate (HR) at rest is associated with adverse cardiovascular events; however, the biologic mechanism for the relation is unclear. We hypothesized a strong association between HR at rest and subclinical inflammation, given their common interrelation with the autonomic nervous system. HR at rest was recorded at baseline in the Multi-Ethnic Study of Atherosclerosis, a cohort of 4 racial or ethnic groups without cardiovascular disease at baseline and then divided into quintiles. Subclinical inflammation was measured using high-sensitivity C-reactive protein, interleukin-6, and fibrinogen. We used progressively adjusted regression models with terms for physical activity and atrioventricular nodal blocking agents in the fully adjusted models. We examined inflammatory markers as both continuous and categorical variables using the clinical cut point of ≥3 mg/L for high-sensitivity C-reactive protein and the upper quartiles of fibrinogen (≥389 mg/dl) and interleukin-6 (≥1.89 pg/ml). Participants had a mean age of 62 years (SD 9.7), mean resting heart rate of 63 beats/min (SD 9.6) and were 47% men. Increased HR at rest was significantly associated with higher levels of all 3 inflammatory markers in both continuous (p for trend <0.001) and categorical (p for trend <0.001) models. Results were similar among all 3 inflammatory markers, and there was no significant difference in the association among the 4 racial or ethnic groups. In conclusion, an increased HR at rest was associated with a higher level of inflammation among an ethnically diverse group of subjects without known cardiovascular disease.
PMCID: PMC4280910  PMID: 24393259
2.  A Multi-Ethnic Meta-Analysis of Genome-Wide Association Studies in Over 100,000 Subjects Identifies 23 Fibrinogen-Associated Loci but no Strong Evidence of a Causal Association between Circulating Fibrinogen and Cardiovascular Disease 
Sabater-Lleal, Maria | Huang, Jie | Chasman, Daniel | Naitza, Silvia | Dehghan, Abbas | Johnson, Andrew D | Teumer, Alexander | Reiner, Alex P | Folkersen, Lasse | Basu, Saonli | Rudnicka, Alicja R | Trompet, Stella | Mälarstig, Anders | Baumert, Jens | Bis, Joshua C. | Guo, Xiuqing | Hottenga, Jouke J | Shin, So-Youn | Lopez, Lorna M | Lahti, Jari | Tanaka, Toshiko | Yanek, Lisa R | Oudot-Mellakh, Tiphaine | Wilson, James F | Navarro, Pau | Huffman, Jennifer E | Zemunik, Tatijana | Redline, Susan | Mehra, Reena | Pulanic, Drazen | Rudan, Igor | Wright, Alan F | Kolcic, Ivana | Polasek, Ozren | Wild, Sarah H | Campbell, Harry | Curb, J David | Wallace, Robert | Liu, Simin | Eaton, Charles B. | Becker, Diane M. | Becker, Lewis C. | Bandinelli, Stefania | Räikkönen, Katri | Widen, Elisabeth | Palotie, Aarno | Fornage, Myriam | Green, David | Gross, Myron | Davies, Gail | Harris, Sarah E | Liewald, David C | Starr, John M | Williams, Frances M.K. | Grant, P.J. | Spector, Timothy D. | Strawbridge, Rona J | Silveira, Angela | Sennblad, Bengt | Rivadeneira, Fernando | Uitterlinden, Andre G | Franco, Oscar H | Hofman, Albert | van Dongen, Jenny | Willemsen, G | Boomsma, Dorret I | Yao, Jie | Jenny, Nancy Swords | Haritunians, Talin | McKnight, Barbara | Lumley, Thomas | Taylor, Kent D | Rotter, Jerome I | Psaty, Bruce M | Peters, Annette | Gieger, Christian | Illig, Thomas | Grotevendt, Anne | Homuth, Georg | Völzke, Henry | Kocher, Thomas | Goel, Anuj | Franzosi, Maria Grazia | Seedorf, Udo | Clarke, Robert | Steri, Maristella | Tarasov, Kirill V | Sanna, Serena | Schlessinger, David | Stott, David J | Sattar, Naveed | Buckley, Brendan M | Rumley, Ann | Lowe, Gordon D | McArdle, Wendy L | Chen, Ming-Huei | Tofler, Geoffrey H | Song, Jaejoon | Boerwinkle, Eric | Folsom, Aaron R. | Rose, Lynda M. | Franco-Cereceda, Anders | Teichert, Martina | Ikram, M Arfan | Mosley, Thomas H | Bevan, Steve | Dichgans, Martin | Rothwell, Peter M. | Sudlow, Cathie L M | Hopewell, Jemma C. | Chambers, John C. | Saleheen, Danish | Kooner, Jaspal S. | Danesh, John | Nelson, Christopher P | Erdmann, Jeanette | Reilly, Muredach P. | Kathiresan, Sekar | Schunkert, Heribert | Morange, Pierre-Emmanuel | Ferrucci, Luigi | Eriksson, Johan G | Jacobs, David | Deary, Ian J | Soranzo, Nicole | Witteman, Jacqueline CM | de Geus, Eco JC | Tracy, Russell P. | Hayward, Caroline | Koenig, Wolfgang | Cucca, Francesco | Jukema, J Wouter | Eriksson, Per | Seshadri, Sudha | Markus, Hugh S. | Watkins, Hugh | Samani, Nilesh J | Wallaschofski, Henri | Smith, Nicholas L. | Tregouet, David | Ridker, Paul M. | Tang, Weihong | Strachan, David P. | Hamsten, Anders | O’Donnell, Christopher J.
Circulation  2013;128(12):10.1161/CIRCULATIONAHA.113.002251.
Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease (CVD), range from 34 to 50%. Genetic variants so far identified by genome-wide association (GWA) studies only explain a small proportion (< 2%) of its variation.
Methods and Results
We conducted a meta-analysis of 28 GWA studies, including more than 90,000 subjects of European ancestry, the first GWA meta-analysis of fibrinogen levels in 7 African Americans studies totaling 8,289 samples, and a GWA study in Hispanic-Americans totaling 1,366 samples. Evaluation for association of SNPs with clinical outcomes included a total of 40,695 cases and 85,582 controls for coronary artery disease (CAD), 4,752 cases and 24,030 controls for stroke, and 3,208 cases and 46,167 controls for venous thromboembolism (VTE). Overall, we identified 24 genome-wide significant (P<5×10−8) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the three structural fibrinogen genes and pathways related to inflammation, adipocytokines and thyrotrophin-releasing hormone signaling. Whereas lead SNPs in a few loci were significantly associated with CAD, the combined effect of all 24 fibrinogen-associated lead SNPs was not significant for CAD, stroke or VTE.
We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and CAD, stroke or VTE.
PMCID: PMC3842025  PMID: 23969696
Fibrinogen; cardiovascular disease; genome-wide association study
3.  Intakes of long-chain n-3 polyunsaturated fatty acids and fish in relation to measurements of subclinical atherosclerosis 
Data on the relations of different types of fish meals and long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs) with measures of atherosclerosis are sparse.
We examined intakes of long-chain n-3 PUFAs and fish in relation to clinical measures of subclinical atherosclerosis.
A cross-sectional study was conducted in 5,488 multiethnic adults aged 45–84 years and free of clinical cardiovascular disease. Diet was assessed using self-administered food frequency questionnaires. Subclinical atherosclerosis was determined by common carotid intima-media thickness (cCIMT, >80th percentile), internal CIMT (iCIMT, >80th percentile), coronary artery calcium score (CAC, >0) or ankle-brachial index (ABI, <0.90), respectively.
After adjustment for potential confounders, intakes of long-chain n-3 PUFAs and non-fried (broiled, steamed, baked or raw) fish were inversely related to subclinical atherosclerosis determined by cCIMT but not iCIMT, CAC or ABI. The multivariable odds ratio comparing the highest to the lowest quartile of dietary exposures in relation to subclinical atherosclerosis determined by cCIMT was 0.69 (95% CI: 0.55, 0.86; p for trend<0.01) for n-3 PUFA intake, 0.80 (95% CI: 0.64, 1.01; p=0.054) for non-fried fish and 0.90 (95% CI: 0.73, 1.10; p=0.33) for fried fish consumption.
This study indicates that dietary intake of long-chain n-3 PUFAs or non-fried fish is associated with lower prevalence of subclinical atherosclerosis classified by cCIMT although significant changes in iCIMT, CAC and ABI were not observed. Our findings also suggest that the association of fish and atherosclerosis may vary depending on the type of fish meal consumed and the measures of atherosclerosis.
PMCID: PMC4151325  PMID: 18842801
long-chain n-3 polyunsaturated fatty acids; fish; fish oil; biomarker; subclinical atherosclerosis; multi-ethnicities
4.  Associations between total serum GGT activity and metabolic risk: MESA 
Biomarkers in medicine  2013;7(5):709-721.
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.
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.
GGT is strongly associated with both cardiovascular and metabolic risk factors, including prevalent metabolic disease, in the MESA cohort.
PMCID: PMC4106917  PMID: 24044563
γ-glutamyltransferase; GGT; glutathione; metabolic syndrome; oxidative stress; Type 2 diabetes
5.  Current employment status, occupational category, occupational hazard exposure, and job stress in relation to telomere length: The Multiethnic Study of Atherosclerosis (MESA) 
Telomere length has been proposed as a biomarker of cell senescence, which is associated with a wide array of adverse health outcomes. While work is a major determinant of health, few studies have investigated the association of telomere length with various dimensions of occupation. Accelerated cellular aging could be a common pathway linking occupational exposure to several health outcomes.
Leukocyte telomere length was assessed using quantitative polymerase chain reaction (Q-PCR) in a community-based sample of 981 individuals (age: 45–84 years old). Questionnaires were used to collect information on current employment status, current or main occupation before retirement, and job strain. The O*NET (Occupational Resource Network) database was linked to the questionnaire data to create 5 exposure measures: physical activity on the job, physical hazard exposure, interpersonal stressors, job control, and job demands. Linear regression was used to estimate associations of occupational characteristics with telomere lengths after adjustment for age, sex, race, socioeconomic position, and several behavioral risk factors.
There were no mean differences in telomere lengths across current employment status, occupational category, job strain categories or levels of most O*NET exposure measures. There was also no evidence that being in lower status occupational categories or being exposed to higher levels of adverse physical or psychosocial exposures accelerated the association between age and telomere shortening.
Cellular aging as reflected by shorter telomeres does not appear to be an important pathway linking occupation to various health outcomes.
PMCID: PMC4068015  PMID: 23686115
6.  n-3 and n-6 Fatty acids are independently associated with lipoprotein-associated phospholipase A2 in the Multi-Ethnic Study of Atherosclerosis 
The British journal of nutrition  2013;110(9):1664-1671.
Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an independent risk factor for CVD and has been proposed as a marker of vascular inflammation. Polyunsaturated n-3 fatty acids (FA) and several n-6 FA are known to suppress inflammation and may influence Lp-PLA2 mass and activity. The associations of n-3 and n-6 plasma FA with Lp-PLA2 mass and activity were analysed using linear regression analysis in 2246 participants of the Multi-Ethnic Study of Atherosclerosis; statistical adjustments were made to control for body mass, inflammation, lipids, diabetes, and additional clinical and demographic factors. Lp-PLA2 mass and activity were significantly lower in participants with the higher n-3 FA EPA (β = −4·72, P<0·001; β = −1·53; P=0·023) and DHA levels (β = −4·47, β = −1·87; both P<0·001). Those in the highest quintiles of plasma EPA and DHA showed 12·71 and 19·15 ng/ml lower Lp-PLA2 mass and 5·7 and 8·90 nmol/min per ml lower Lp-PLA2 activity than those in the first quintiles, respectively. In addition, lower Lp-PLA2 mass and activity were associated with higher levels of n-6 arachidonic acid (β = −1·63, β = −1·30; both P<0·001), while γ-linolenic acid was negatively associated with activity (β = −27·7, P=0·027). Lp-PLA2 mass was significantly higher in participants with greater plasma levels of n-6 linoleic (β = 0·828, P=0·011) and dihomo-γ-linolenic acids (β = 4·17, P=0·002). Based on their independent associations with Lp-PLA2 mass and activity, certain n-3 and n-6 FA may have additional influences on CVD risk. Intervention studies are warranted to assess whether these macronutrients may directly influence Lp-PLA2 expression or activity.
PMCID: PMC4060439  PMID: 23551952
Fatty acids; n-3; Atherosclerosis; Lipoprotein-associated phospholipase; Lipoprotein-associated phospholipase A2
7.  Lack of Associations of Ten Candidate Coronary Heart Disease Risk Genetic Variants and Subclinical Atherosclerosis in Four U.S. Populations: the Population Architecture using Genomics and Epidemiology (PAGE) Study 
Atherosclerosis  2013;228(2):390-399.
A number of genetic variants have been discovered by recent genome-wide association studies for their associations with clinical coronary heart disease (CHD). However, it is unclear whether these variants are also associated with the development of CHD as measured by subclinical atherosclerosis phenotypes, ankle brachial index (ABI), carotid artery intima-media thickness (cIMT) and carotid plaque.
Ten CHD risk single nucleotide polymorphisms (SNPs) were genotyped in individuals of European American (EA), African American (AA), American Indian (AI), and Mexican American (MA) ancestry in the Population Architecture using Genomics and Epidemiology (PAGE) study. In each individual study, we performed linear or logistic regression to examine population-specific associations between SNPs and ABI, common and internal cIMT, and plaque. The results from individual studies were meta-analyzed using a fixed effect inverse variance weighted model.
None of the ten SNPs was significantly associated with ABI and common or internal cIMT, after Bonferroni correction. In the sample of 13,337 EA, 3,809 AA, and 5,353 AI individuals with carotid plaque measurement, the GCKR SNP rs780094 was significantly associated with the presence of plaque in AI only (OR = 1.32, 95% confidence interval: 1.17, 1.49, P = 1.08 × 10−5), but not in the other populations (P = 0.90 in EA and P = 0.99 in AA). A 9p21 region SNP, rs1333049, was nominally associated with plaque in EA (OR = 1.07, P = 0.02) and in AI (OR = 1.10, P = 0.05).
We identified a significant association between rs780094 and plaque in AI populations, which needs to be replicated in future studies. There was little evidence that the index CHD risk variants identified through genome-wide association studies in EA influence the development of CHD through subclinical atherosclerosis as assessed by cIMT and ABI across ancestries.
PMCID: PMC3717342  PMID: 23587283
ankle brachial index; carotid artery intima-media thickness; carotid plaque; coronary heart disease; genetic association study; multiethnic populations; subclinical atherosclerosis
8.  Pentraxin-3 and the right ventricle: the Multi-Ethnic Study of Atherosclerosis–Right Ventricle Study 
Pulmonary Circulation  2014;4(2):250-259.
Pentraxin-3 (PTX3) is a protein mediator of innate immunity that is elevated in the setting of left heart disease and pulmonary arterial hypertension. The relationship between PTX3 and right ventricular (RV) structure and function is not known. We included men and women with magnetic resonance imaging assessment of RV structure and function and measurement of PTX3 from the Multi-Ethnic Study of Atherosclerosis, a study of individuals free of clinical cardiovascular disease. Multivariable linear regression estimated associations between PTX3 protein levels and RV measures after adjusting for demographic characteristics, anthropometrics, smoking status, diabetes mellitus, hypertension, and corresponding left ventricular (LV) parameters. Instrumental variable analysis exploiting Mendelian randomization was attempted using two-stage least squares regression. The study sample included 1,779 participants with available PTX3 levels, RV measures, and all covariables. Mean PTX3 level was 2.1 ng/mL. Higher PTX3 was independently associated with greater RV mass and larger RV end-diastolic volume with and without adjustment for the corresponding LV parameters or C-reactive protein (all P < .05). There was no association between PTX3 and RV ejection fraction or stroke volume. Single-nucleotide polymorphisms were not associated with PTX3 protein levels or RV measures after accounting for race. Instrumental variable analysis could not be reliably performed. Higher PTX3 protein levels were associated with greater RV mass and larger RV end-diastolic volume. These associations were independent of common cardiovascular risk factors and LV morphologic changes. Inflammation is associated with differences in the pulmonary circulation-RV axis in adults without clinical cardiovascular disease.
PMCID: PMC4070771  PMID: 25006444
pulmonary hypertension; heart failure; inflammation; right ventricle; Mendelian randomization
9.  Association of Functional Polymorphism rs2231142 (Q141K) in the ABCG2 Gene With Serum Uric Acid and Gout in 4 US Populations 
American Journal of Epidemiology  2013;177(9):923-932.
A loss-of-function mutation (Q141K, rs2231142) in the ATP-binding cassette, subfamily G, member 2 gene (ABCG2) has been shown to be associated with serum uric acid levels and gout in Asians, Europeans, and European and African Americans; however, less is known about these associations in other populations. Rs2231142 was genotyped in 22,734 European Americans, 9,720 African Americans, 3,849 Mexican Americans, and 3,550 American Indians in the Population Architecture using Genomics and Epidemiology (PAGE) Study (2008–2012). Rs2231142 was significantly associated with serum uric acid levels (P = 2.37 × 10−67, P = 3.98 × 10−5, P = 6.97 × 10−9, and P = 5.33 × 10−4 in European Americans, African Americans, Mexican Americans, and American Indians, respectively) and gout (P = 2.83 × 10−10, P = 0.01, and P = 0.01 in European Americans, African Americans, and Mexican Americans, respectively). Overall, the T allele was associated with a 0.24-mg/dL increase in serum uric acid level (P = 1.37 × 10−80) and a 1.75-fold increase in the odds of gout (P = 1.09 × 10−12). The association between rs2231142 and serum uric acid was significantly stronger in men, postmenopausal women, and hormone therapy users compared with their counterparts. The association with gout was also significantly stronger in men than in women. These results highlight a possible role of sex hormones in the regulation of ABCG2 urate transporter and its potential implications for the prevention, diagnosis, and treatment of hyperuricemia and gout.
PMCID: PMC4023295  PMID: 23552988
ABCG2 protein, human; genetic association studies; gout; meta-analysis; polymorphism, single nucleotide; urate transporter; uric acid
10.  13-Year Long-Term Associations between Changes in Traditional Cardiovascular Risk Factors and Changes in Fibrinogen Levels: The Coronary Artery Risk Development in Young Adults (CARDIA) Study 
Atherosclerosis  2012;226(1):214-219.
Cross-sectional and prospective studies have linked cardiovascular events and traditional risk factors (TRFs) with higher plasma fibrinogen levels. In a young cohort, we sought to determine longitudinal associations between changes in/development of TRFs and fibrinogen levels over 13 years.
We included 2525 adults from the CARDIA study, aged 25-37 with fibrinogen and TRFs measured at year 7 (study baseline; 1992-1993); and year 20 (follow-up). Multiple linear regressions were used to compare mean changes in fibrinogen to TRFs.
Mean fibrinogen increased by 71mg/dL vs. 70mg/dL (p=NS) in black vs. white men, and 78mg/dL vs. 68mg/dL (p<0.05) in black vs. white women, respectively over 13 years. After multivariable adjustments, fibrinogen generally rose with increasing BMI (p<0.001; all sex/race groups), LDL-cholesterol, log triglycerides and diastolic blood pressure; and fell with increasing HDL-cholesterol and physical activity. 13-year increase in fibrinogen for persons who quit smoking or became non-obese were comparable (p=NS) to that of never-smokers and never-obese persons.
Among young black and white men and women with few baseline cardiovascular risk factors, fibrinogen tracked longitudinally with changes in TRFs over 13 years through middle-age. There was a strong inverse longitudinal relationship between modifiable risk factors (weight loss/smoking cessation) and 13-year change in fibrinogen. Our study helps provide some insight into the role of fibrinogen as a disease marker in the associations between fibrinogen and CVD.
PMCID: PMC3529787  PMID: 23177973
Fibrinogen; risk factors; cardiovascular disease prevention; obesity; smoking; sex; race
11.  Soluble CD14: genome-wide association analysis and relationship to cardiovascular risk and mortality in the older adults 
Arteriosclerosis, thrombosis, and vascular biology  2012;33(1):10.1161/ATVBAHA.112.300421.
CD14 is a glycosylphosphotidylinositol-(GPI)-anchored membrane glycoprotein expressed on neutrophils and monocytes/macrophages that also circulates as a soluble form (sCD14). Despite the well-recognized role of CD14 in inflammation, relatively little is known about the genetic determinants of sCD14 or the relationship of sCD14 to vascular- and aging-related phenotypes.
Methods and Results
We measured baseline levels of sCD14 in over 5,000 European-American (EA) and African-American (AA) adults 65 years and older from the Cardiovascular Health Study, who were well-characterized at baseline for atherosclerotic risk factors and subclinical cardiovascular disease (CVD), and who have been followed for clinical CVD and mortality outcomes up to 20 years. At baseline, sCD14 generally showed strong positive correlations with traditional cardio-metabolic risk factors and with subclinical measures of vascular disease such as carotid wall thickness and ankle-brachial index (independently of traditional CVD risk factors), and was also inversely correlated with body mass index. In genome-wide association analyses of sCD14, we (a) confirmed the importance of the CD14 locus on chromosome 5q21 in EA; (b) identified a novel African ancestry-specific allele of CD14 associated with lower sCD14 in AA; (c) identified a putative novel association in EA of a non-synonymous variant of PIGC, which encodes an enzyme required for the first step in GPI anchor biosynthesis. Finally, we show that, like other acute phase inflammatory biomarkers, sCD14 predicts incident CVD, and strongly and independently predicts all-cause mortality in older adults.
CD14 independently predicts risk mortality in older adults.
PMCID: PMC3826541  PMID: 23162014
CD14; glycosylphosphotidylinositol; coronary heart disease; mortality
12.  Associations of BMI and insulin resistance with leptin, adiponectin, and the leptin to adiponectin ratio across ethnic groups: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Annals of epidemiology  2012;22(10):705-709.
Associations of adiponectin and leptin and their ratio with BMI and HOMA-IR have been investigated in different ethnic groups but variability in both assays and statistical methods have made cross-study comparisons difficult. We examined associations among these variables across four ethnic groups in a single study.
Adiponectin and leptin were measured in a subset of MESA participants. We calculated associations (using both partial correlations and adjusted linear regression) in each ethnic group and then compared the magnitude of these associations across groups.
After excluding individuals with type 2 diabetes there were 714 White, 219 Chinese, 332 African American, and 405 Hispanic individuals, in the study sample. Associations of BMI with adiponectin and leptin differed significantly (P < 0.05) across the ethnic groups in regression analyses, while associations of HOMA-IR with adiponectin and leptin did not differ across ethnic groups. The leptin to adiponectin ratio was not associated with a greater amount of adiposity or HOMA-IR variance than leptin or adiponectin in any ethnic group.
Given the consistency of HOMA-IR and adipokine associations, the differing means of adiponectin and leptin across ethnic groups may help to explain ethnic differences in mean insulin resistance.
PMCID: PMC3459265  PMID: 22929534
13.  Long-term Assessment of Inflammation and Healthy Aging in Late Life: The Cardiovascular Health Study All Stars 
Associations of inflammation with age-related pathologies are documented; however, it is not understood how changes in inflammation over time impact healthy aging.
We examined associations of long-term change in C-reactive protein (CRP) and interleukin-6 (IL-6) with concurrent onset of physical and cognitive impairment, subsequent cardiovascular disease (CVD), and mortality in 1,051 participants in the Cardiovascular Health Study All Stars Study. Biomarkers were measured in 1996–1997 and 2005–2006.
In 2005–2006, median age was 84.9 years, 63% were women and 17% non-white; 21% had at least a doubling in CRP over time and 23% had at least a doubling in IL-6. Adjusting for demographics, CVD risk factors, and 1996–1997 CRP level, each doubling in CRP change over 9 years was associated with higher risk of physical or cognitive impairment (odds ratio 1.29; 95% confidence interval 1.15, 1.45). Results were similar for IL-6 (1.45; 1.20, 1.76). A doubling in IL-6 change over time, but not CRP, was associated with incident CVD events; hazard ratio (95% confidence interval) 1.34 (1.03, 1.75). Doubling in change in each biomarker was individually associated with mortality (CRP: 1.12 [1.03, 1.22]; IL-6 1.39 [1.16, 1.65]). In models containing both change and 2005–2006 level, only level was associated with CVD events and mortality.
Although increases in inflammation markers over 9 years were associated with higher concurrent risk of functional impairment and subsequent CVD events and mortality, final levels of each biomarker appeared to be more important in determining risk of subsequent events than change over time.
PMCID: PMC3436091  PMID: 22367431
Inflammation; Aging; Physical function; Cognitive function
14.  Decreased Naive and Increased Memory CD4+ T Cells Are Associated with Subclinical Atherosclerosis: The Multi-Ethnic Study of Atherosclerosis 
PLoS ONE  2013;8(8):e71498.
Adaptive immunity has been implicated in atherosclerosis in animal models and small clinical studies. Whether chronic immune activation is associated with atherosclerosis in otherwise healthy individuals remains underexplored. We hypothesized that activation of adaptive immune responses, as reflected by higher proportions of circulating CD4+ memory cells and lower proportions of naive cells, would be associated with subclinical atherosclerosis.
Methods and Findings
We examined cross-sectional relationships of circulating CD4+ naive and memory T cells with biomarkers of inflammation, serologies, and subclinical atherosclerosis in 912 participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Circulating CD4+ naive cells were higher in women than men and decreased with age (all p-values <0.0001). European-Americans had higher levels of naive cells and lower levels of memory cells compared with African-Americans and Hispanic-Americans (all p-values ≤0.0005). Lower naive/higher memory cells were associated with interleukin-6 levels. In multivariate models, cytomegalovirus (CMV) and H. Pylori titers were strongly associated with higher memory and lower naive cells (all p-values <0.05). Higher memory cells were associated with coronary artery calcification (CAC) level in the overall population [β-Coefficient (95% confidence interval (CI))  = 0.20 (0.03, 0.37)]. Memory and naive (inversely) cells were associated with common carotid artery intimal media thickness (CC IMT) in European-Americans [memory: β =  0.02 (0.006, 0.04); naive: β = −0.02 (−0.004, −0.03)].
These results demonstrate that the degree of chronic adaptive immune activation is associated with both CAC and CC IMT in otherwise healthy individuals, consistent with the known role of CD4+ T cells, and with innate immunity (inflammation), in atherosclerosis. These data are also consistent with the hypothesis that immunosenescence accelerates chronic diseases by putting a greater burden on the innate immune system, and suggest the importance of prospective studies and research into strategies to modulate adaptive immune activation in chronic disease states such as atherosclerosis.
PMCID: PMC3751895  PMID: 24009662
15.  T‐Helper Type 1 Bias in Healthy People Is Associated With Cytomegalovirus Serology and Atherosclerosis: The Multi‐Ethnic Study of Atherosclerosis 
Although T‐helper type 1 (Th1) cells are considered important in atherosclerosis, the relationships between Th1 and Th2 cells and atherosclerosis have not been examined in population‐based studies.
Methods and Results
We measured Th cells as a percentage of lymphocytes by flow cytometry using CD4 staining (%CD4) in 917 participants of the Multi‐Ethnic Study of Atherosclerosis. We also measured interferon gamma–positive and interleukin‐4‐positive CD4+ cells, representing Th1 and Th2 subpopulations (%Th1 and %Th2), respectively. We found that %CD4 was 1.5% lower per 10 years of age (P<0.0001). Whites had higher %CD4 and lower %Th1 and %Th2 values than other race/ethnic groups. Body mass index (BMI) and blood pressure were associated with %CD4, but no traditional cardiovascular disease (CVD) risk factors were associated with %Th1 or %Th2. In multivariable models, the major independent variable associated with %Th1 was cytomegalovirus (CMV) antibody titer, with minor contributions from age, sex, seasonality, and interleukin‐6. In models with coronary artery calcification level as the outcome, significant independent variables included age, sex, smoking status, and %Th1 (β=0.25; P≤0.01). Both %Th1 and %Th2 were associated with common carotid intimal media thickness (β=0.02 and −0.02, respectively; both P<0.05), as were age, sex, race/ethnicity, blood pressure, and BMI.
Th1 bias is associated with subclinical atherosclerosis in a multiethnic population. The main Th1 correlate was CMV infectious burden. These findings are consistent with a role of Th1 cells in atherosclerosis and suggest the importance of prospective studies of T‐helper cell biasing in CVD.
PMCID: PMC3698770  PMID: 23688675
atherosclerosis; epidemiology; immunology; inflammation; T‐helper cell
16.  Telomere-associated polymorphisms correlate with cardiovascular disease mortality in Caucasian women: The Cardiovascular Health Study 
Leukocyte telomere length (LTL) is linked to cardiovascular disease (CVD); however, it is unclear if LTL has an etiologic role in CVD. To gain insight into the LTL and CVD relationship, a cohort study of CVD mortality and single nucleotide polymorphisms (SNPs) in OBFC1 and TERC, genes related to LTL, was conducted among 3271 Caucasian participants ages ≥65 years enrolled 1989–1990 in the Cardiovascular Health Study. Leukocyte DNA was genotyped for SNPs in OBFC1 (rs4387287 and rs9419958) and TERC (rs3772190) that were previously associated with LTL through genome-wide association studies. Cox regression was used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). The OBFC1 SNPs were in linkage disequilibrium (r2=0.99), and both SNPs were similarly associated with CVD mortality in women. For women, there was a decreased risk of CVD death associated with the minor allele (rs4387287), HR=0.7; 95% CI: 0.5–0.9 (CC vs. AC) and HR=0.5; 95% CI: 0.20–1.4 (CC vs. AA) (p-trend <0.01). For men there was no association, HR=1.0; 95% CI: 0.7–1.3 (CC vs. AC) and HR=1.7; 95% CI: 0.8–3.6 (CC vs. AA) (p-trend=0.64). These findings support the hypothesis that telomere biology and associated genes may play a role in CVD-related death, particularly among women.
PMCID: PMC3391009  PMID: 22449406
17.  Tooth Loss, Systemic Inflammation, and Prevalent Stroke Among Participants in the Reasons for Geographic and Racial Difference in Stroke (REGARDS) Study 
Atherosclerosis  2008;203(2):615-619.
Background and Purpose
Periodontal disease results in tooth loss, may contribute to systemic inflammation, and is associated with stroke. We examined cross-sectional associations between tooth loss, inflammation markers, stroke, race, and geographic region among participants in the REasons for Geographic And Racial Differences in Stroke (REGARDS) Study of whites and blacks ≥45 years.
We studied 24393 participants. Associations of tooth loss and inflammation markers (C-reactive protein (CRP), white blood cell count (WBC) and albumin) were examined by linear regression, and associations of tooth loss with geographic region, race, and prevalent stroke by logistic regression.
Compared to whites, blacks had an odds ratio of 1.48 (95% confidence interval 1.37–1.60) of having more teeth lost. There were no geographic differences in tooth loss. Compared to no tooth loss, those with 17–32 teeth lost had 1.17 mg/L higher CRP (p < 0.0001) and 0.18 ×109/L higher WBC (p = 0.008), did not differ in albumin, and had an odds ratio of prevalent stroke of 1.28 (1.09–1.49). Those with 1–16 teeth lost did not differ in CRP and WBC, had 0.03 g/dL higher albumin (p = 0.004), and had no increased stroke prevalence. CRP or WBC did not attenuate associations between tooth loss and stroke.
Tooth loss, which varied with race, but not region of residence, was associated with inflammation markers and stroke. The latter association was not confounded by inflammation markers.
PMCID: PMC3633204  PMID: 18801482
Tooth Loss; Inflammation factors; Stroke; region of residence; race
18.  Cholesteryl Ester Transfer Protein Genetic Polymorphisms, HDL Cholesterol, and Subclinical Cardiovascular Disease in the Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2008;200(2):359-367.
The cholesteryl ester transport protein (CETP) plays a key role in high-density lipoprotein (HDL) metabolism. Genetic variants that alter CETP activity and concentration may cause significant alterations in HDL-cholesterol (HDL-C) concentration; however, controversies remain about whether these genetic variants are associated with atherosclerosis. We genotyped the CETP R451Q, A373P, -629C/A, Taq1B, and -2505C/A polymorphisms in a cohort of Caucasian, Chinese, African-American, and Hispanic individuals within the Multi-Ethnic Study of Atherosclerosis. Genotypes were examined in relationship to HDL-C, CETP activity, CETP concentration, and three measures of subclinical cardiovascular disease (CVD): coronary artery calcium (CAC) measured by fast CT scanning, and carotid intimal-medial thickness (IMT) and carotid artery plaque, measured by ultrasonography. Carriers of the 451Q and 373P alleles have significantly higher CETP concentration (22.4% and 19.5%, respectively; p<0.001) and activity (13.1% and 9.4%, respectively; p<0.01) and lower HDL-C (5.6% and 6.0%, respectively; p<0.05). The minor alleles of the R451Q and A373P polymorphisms are associated with the presence of CAC, even after adjusting for CVD risk factors and HDL-C (p=0.006 and p=0.01, respectively). The R451Q polymorphism is also associated with presence of carotid artery plaque (p=0.036). Neither polymorphism is associated with common or internal carotid IMT. We confirmed that the -629A, Taq1B B2, and -2505A alleles are significantly associated with lower CETP concentration (20.8%, 25.0%, and 23.7%, respectively; p<0.001) and activity (14.8%, 19.8%, and 18.4%, respectively; p<0.001) and higher HDL-C concentration (9.7%, 11.5%, and 10.4%, respectively; p<0.01). However, we did not find any associations between these non-coding polymorphisms and subclinical CVD.
PMCID: PMC3612981  PMID: 18243217
19.  Social Factors and Leukocyte DNA Methylation of Repetitive Sequences: The Multi-Ethnic Study of Atherosclerosis 
PLoS ONE  2013;8(1):e54018.
Epigenetic changes are a potential mechanism contributing to race/ethnic and socioeconomic disparities in health. However, there is scant evidence of the race/ethnic and socioeconomic patterning of epigenetic marks. We used data from the Multi-Ethnic Study of Atherosclerosis Stress Study (N = 988) to describe age- and gender- independent associations of race/ethnicity and socioeconomic status (SES) with methylation of Alu and LINE-1 repetitive elements in leukocyte DNA. Mean Alu and Line 1 methylation in the full sample were 24% and 81% respectively. In multivariable linear regression models, African-Americans had 0.27% (p<0.01) and Hispanics 0.20% (p<0.05) lower Alu methylation than whites. In contrast, African-Americans had 0.41% (p<0.01) and Hispanics 0.39% (p<0.01) higher LINE-1 methylation than whites. These associations remained after adjustment for SES. In addition, a one standard deviation higher wealth was associated with 0.09% (p<0.01) higher Alu and 0.15% (p<0.01) lower LINE-1 methylation in age- and gender- adjusted models. Additional adjustment for race/ethnicity did not alter this pattern. No associations were observed with income, education or childhood SES. Our findings, from a large community-based sample, suggest that DNA methylation is socially patterned. Future research, including studies of gene-specific methylation, is needed to understand better the opposing associations of Alu and LINE-1 methylation with race/ethnicity and wealth as well as the extent to which small methylation changes in these sequences may influence disparities in health.
PMCID: PMC3539988  PMID: 23320117
20.  Prevalence of Traditional Modifiable Cardiovascular Risk Factors in Patients with Rheumatoid Arthritis: Comparison with Control Subjects from the Multi-Ethnic Study of Atherosclerosis 
Despite the recognized risk of accelerated atherosclerosis in patients with rheumatoid arthritis (RA), little is known about cardiovascular risk management in contemporary cohorts of these patients. We tested the hypotheses that major modifiable cardiovascular risk factors were more frequent and rates of treatment, detection, and control were lower in patients with RA than in non-RA controls.
The prevalence of hypertension, diabetes, elevated low-density lipoprotein (LDL) cholesterol, elevated body mass index, smoking, moderate-high 10-year cardiovascular risk and the rates of underdiagnosis, therapeutic treatment, and recommended management were compared in 197 RA patients and 274 frequency-matched control subjects, and their associations with clinical characteristics were examined.
Eighty percent of RA patients and 81% of control subjects had at least 1 modifiable traditional cardiovascular risk factor. Hypertension was more prevalent in the RA group (57%) than in controls [42%, P =0.001]. There were no statistically significant differences in the frequency of diabetes, elevated body mass index, smoking, intermediate-high 10-year coronary heart disease risk, or elevated LDL in patients with RA versus controls. Rates of newly identified diabetes, hypertension, and hyperlipidemia were similar in RA patients versus controls. Rates of therapeutic interventions were low in both groups but their use was associated with well-controlled blood pressure (OR = 4.55, 95% CI: 1.70, 12.19) and lipid levels (OR = 9.90, 95% CI: 3.30, 29.67).
Hypertension is more common in RA than in controls. Other traditional cardiovascular risk factors are highly prevalent, underdiagnosed, and poorly controlled in patients with RA, as well as controls.
PMCID: PMC3538033  PMID: 22340996
rheumatoid arthritis; cardiovascular risk; epidemiology
21.  High sodium:potassium intake ratio increases the risk for all-cause mortality: the REasons for Geographic And Racial Differences in Stroke (REGARDS) study 
Increased dietary Na intake and decreased dietary K intake are associated with higher blood pressure. It is not known whether the dietary Na:K ratio is associated with all-cause mortality or stroke incidence and whether this relationship varies according to race. Between 2003 and 2007, the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort enrolled 30 239 black and white Americans aged 45 years or older. Diet was assessed using the Block 98 FFQ and was available on 21 374 participants. The Na:K ratio was modelled in race- and sex-specific quintiles for all analyses, with the lowest quintile (Q1) as the reference group. Data on other covariates were collected using both an in-home assessment and telephone interviews. We identified 1779 deaths and 363 strokes over a mean of 4·9 years. We used Cox proportional hazards models to obtain multivariable-adjusted hazard ratios (HR). In the highest quintile (Q5), a high Na:K ratio was associated with all-cause mortality (Q5 v. Q1 for whites: HR 1·22; 95 % CI 1·00, 1·47, P for trend = 0·084; for blacks: HR 1·36; 95 % CI 1·04, 1·77, P for trend = 0·028). A high Na:K ratio was not significantly associated with stroke in whites (HR 1·29; 95 % CI 0·88, 1·90) or blacks (HR 1·39; 95 % CI 0·78, 2·48), partly because of the low number of stroke events. In the REGARDS study, a high Na:K ratio was associated with all-cause mortality and there was a suggestive association between the Na:K ratio and stroke. These data support the policies targeted at reduction of Na from the food supply and recommendations to increase K intake.
PMCID: PMC4153038  PMID: 25191561
Stroke; Death; Race; Sodium; HR, hazard ratio; REGARDS, REasons for Geographic And Racial Differences in Stroke
22.  Kidney Function Decline in the Elderly: Impact of Lipoprotein-Associated Phospholipase A2 
American Journal of Nephrology  2011;34(6):512-518.
Background: Whether lipoprotein-associated phospholipase A2 (Lp-PLA2) levels are associated with kidney function decline has not been well studied. Methods: We investigated associations of Lp-PLA2 antigen and activity with kidney function decline and rapid decline over 5.7 years in the Cardiovascular Health Study (n = 4,359). We estimated kidney function by cystatin C (eGFRcys) in repeated measures, and defined rapid decline as ≥3 ml/min/1.73 m2 per year. We stratified by baseline preserved GFR (≥60 ml/min/1.73 m2). Results: Mean age was 72 ± 5 years. Average eGFRcys decline was −1.79 ml/min/1.73 m2 (SD = 2.60) per year. Among persons with preserved GFR, compared to the lowest quartile of Lp-PLA2 antigen, eGFRcys decline was faster among persons in the second, β −0.31 (95% CI −0.52, −0.10), third −0.19 (–0.41, 0.02) and fourth quartiles −0.26 (–0.48, −0.04) after full adjustment. Persons in the highest quartile of Lp-PLA2 antigen had increased odds of rapid decline 1.34 (1.03, 1.75), compared to the lowest. There was no significant association between levels of Lp-PLA2 activity and eGFRcys decline or rapid decline. Associations were not statistically significant among persons with low eGFR (<60 ml/min/1.73 m2) at baseline. Conclusion: Higher levels of Lp-PLA2 antigen but not activity were significantly associated with faster rates of kidney function decline. These findings may suggest a novel vascular pathway for kidney disease progression.
PMCID: PMC3225232  PMID: 22056971
Chronic kidney disease; Elderly; Estimated GFR; Kidney decline; Lipoprotein-associated phospholipase A2
23.  Association of Genetic Variants and Incident Coronary Heart Disease in Multi-Ethnic Cohorts. The PAGE Study 
Genome wide association studies identified several single nucleotide polymorphisms (SNPs) associated with prevalent coronary heart disease (CHD) but less is known of associations with incident CHD. The association of thirteen published CHD SNPs was examined in five ancestry groups of four large US prospective cohorts.
Methods and Results
The analyses included incident coronary events over 9.1 to 15.7 average follow-up times in up to 26,617 white individuals (6,626 events), 8,018 African Americans (914 events), 1,903 Hispanics (113 events), 3,669 American Indians (595 events) and 885 Asian/Pacific Islanders (66 events). We used Cox proportional hazards models (with additive mode of inheritance) adjusted for age, sex and ancestry (as needed). Nine loci were statistically associated with incident CHD events in whites: 9p21 (rs10757278, p=4.7 × 10−41), 16q23.1 (rs2549513, p=0.0004), 6p24.1 (rs499818, p=0.0002), 2q36.3 (rs2943634, p=6.7 × 10−6), MTHFDIL (rs6922269, p=5.1 × 10−10), APOE (rs429358, p=2.7 × 10−18), ZNF627 (rs4804611, p=5.0 × 10−8), CXCL12 (rs501120, p=1.4 × 10−6) and LPL (rs268, p=2.7 × 10−17). The 9p21 region showed significant between-study heterogeneity, with larger effects in individuals aged 55 years or younger and in women. Inclusion of coronary revascularization procedures among the incident CHD events introduced heterogeneity. The SNPs were not associated with CHD in African Americans and associations varied in other US minorities.
Prospective analyses of white individuals replicated several reported cross-sectional CHD-SNP associations.
PMCID: PMC3293207  PMID: 22042884
9p21 locus; incident coronary heart disease; genetic polymorphisms
24.  Longitudinal Changes in Adiponectin and Inflammatory Markers and Relation to Survival in the Oldest Old: The Cardiovascular Health Study All Stars Study 
Adiponectin has anti-inflammatory properties, and its production is suppressed by inflammatory factors. Although elevated levels of adiponectin and inflammatory markers each predict mortality in older adults, the implications of their interdependent actions have not been examined.
We investigated the joint associations of levels and interval changes in adiponectin, C-reactive protein (CRP), and interleukin 6 (IL-6) with risk of death in 840 older adults participating in a population-based study. Adiponectin, CRP, and IL-6 were measured in samples collected 8.9 (8.2–9.8) years apart, and all-cause mortality was subsequently ascertained (n = 176).
Interval changes and end levels of adiponectin, CRP, and IL-6 showed mostly positive, independent associations with mortality, without evidence of multiplicative interaction. Joint models, however, showed an U-shaped relationship between end level of adiponectin and outcome (hazard ratio [HR] [95% CI] = 0.72 [0.52–0.99] per standard deviation [SD] for levels <20.0 mg/L; HR = 1.91 [1.61–3.44] per SD for levels ≥20.0 mg/L). Participants with the greatest longitudinal increases (upper quartile) in both adiponectin and inflammatory markers had a higher risk of death (HR = 2.85 [1.78–4.58]) than those with large increases in adiponectin alone (HR = 1.87 [1.20–2.92]) (p = .043), but not inflammatory markers alone (HR = 2.48 [1.67–3.67]) (p = .55), as compared with smaller changes for both.
Higher levels or interval change in adiponectin and inflammatory markers predict increased mortality in older persons independent of each other, although for adiponectin, the association appears inverse below 20 mg/L. These findings suggest that inflammatory and noninflammatory mechanisms governing aging-related decline operate in parallel and provide a potential explanation for paradoxical adiponectin–outcome associations reported previously.
PMCID: PMC3172562  PMID: 21659339
Adiponectin; C-reactive protein; Interleukin 6; Aging; Mortality
Vitamin D deficiency and parathyroid hormone (PTH) excess are common among older adults and may adversely impact cardiovascular health. We evaluated associations of 25-hydroxyvitamin D (25-OHD) and PTH concentrations, separately, and in combination, with incident cardiovascular events and mortality during 14 years of follow-up in the Cardiovascular Health Study.
Methods and results
We studied 2,312 participants who were free of cardiovascular disease at baseline. We measured 25-OHD and intact PTH from previously frozen serum using mass spectrometry and a two-site immunoassay. Outcomes were adjudicated cases of myocardial infarction, heart failure, cardiovascular death, and all cause mortality. There were 384 participants (17%) who had serum 25-OHD concentrations <15 ng/ml and 570 (25%) who had serum PTH concentrations ≥ 65 pg/ml. After adjustment, each 10-ng/ml lower 25-OHD concentration was associated with a 9% greater (95% CI 2% to 17% greater) relative hazard of mortality and a 25% greater (95% CI 8% to 44% greater) relative hazard of myocardial infarction. Serum 25-OHD concentrations <15 ng/ml, were associated with a 29% greater (95% CI 5% to 55% greater) risk of mortality. Serum PTH concentrations ≥ 65 pg/ml were associated with a 30% greater risk of heart failure (95% CI 6% to 61% greater), but not other outcomes. There was no evidence of an interaction between serum 25-OHD and PTH concentrations and cardiovascular events.
Among older adults, 25-OHD deficiency is associated with myocardial infarction and mortality; PTH excess is associated with heart failure. Vitamin D and PTH might influence cardiovascular risk through divergent pathways.
PMCID: PMC3210558  PMID: 21939825
Vitamin D; parathyroid hormone; myocardial infarction; cardiovascular death; heart failure; mortality; mineral metabolism

Results 1-25 (66)