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1.  Current employment status, occupational category, occupational hazard exposure, and job stress in relation to telomere length: The Multiethnic Study of Atherosclerosis (MESA) 
Objective
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.
Methods
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.
Results
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.
Conclusions
Cellular aging as reflected by shorter telomeres does not appear to be an important pathway linking occupation to various health outcomes.
doi:10.1136/oemed-2012-101296
PMCID: PMC4068015  PMID: 23686115
2.  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.
doi:10.1017/S0007114513000949
PMCID: PMC4060439  PMID: 23551952
Fatty acids; n-3; Atherosclerosis; Lipoprotein-associated phospholipase; Lipoprotein-associated phospholipase A2
3.  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.
Background
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1016/j.atherosclerosis.2013.02.038
PMCID: PMC3717342  PMID: 23587283
ankle brachial index; carotid artery intima-media thickness; carotid plaque; coronary heart disease; genetic association study; multiethnic populations; subclinical atherosclerosis
4.  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.
doi:10.1086/675988
PMCID: PMC4070771  PMID: 25006444
pulmonary hypertension; heart failure; inflammation; right ventricle; Mendelian randomization
5.  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.
doi:10.1093/aje/kws330
PMCID: PMC4023295  PMID: 23552988
ABCG2 protein, human; genetic association studies; gout; meta-analysis; polymorphism, single nucleotide; urate transporter; uric acid
6.  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.
Objective
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.atherosclerosis.2012.10.043
PMCID: PMC3529787  PMID: 23177973
Fibrinogen; risk factors; cardiovascular disease prevention; obesity; smoking; sex; race
7.  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.
Objective
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.
Conclusion
CD14 independently predicts risk mortality in older adults.
doi:10.1161/ATVBAHA.112.300421
PMCID: PMC3826541  PMID: 23162014
CD14; glycosylphosphotidylinositol; coronary heart disease; mortality
8.  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.
Purpose
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.annepidem.2012.07.011
PMCID: PMC3459265  PMID: 22929534
9.  Long-term Assessment of Inflammation and Healthy Aging in Late Life: The Cardiovascular Health Study All Stars 
Background.
Associations of inflammation with age-related pathologies are documented; however, it is not understood how changes in inflammation over time impact healthy aging.
Methods.
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.
Results.
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.
Conclusions.
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.
doi:10.1093/gerona/glr261
PMCID: PMC3436091  PMID: 22367431
Inflammation; Aging; Physical function; Cognitive function
10.  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.
Background
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)].
Conclusions
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.
doi:10.1371/journal.pone.0071498
PMCID: PMC3751895  PMID: 24009662
11.  T‐Helper Type 1 Bias in Healthy People Is Associated With Cytomegalovirus Serology and Atherosclerosis: The Multi‐Ethnic Study of Atherosclerosis 
Background
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.
Conclusions
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.
doi:10.1161/JAHA.113.000117
PMCID: PMC3698770  PMID: 23688675
atherosclerosis; epidemiology; immunology; inflammation; T‐helper cell
12.  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.
doi:10.1016/j.mad.2012.03.002
PMCID: PMC3391009  PMID: 22449406
13.  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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.atherosclerosis.2008.07.037
PMCID: PMC3633204  PMID: 18801482
Tooth Loss; Inflammation factors; Stroke; region of residence; race
14.  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.
doi:10.1016/j.atherosclerosis.2007.12.038
PMCID: PMC3612981  PMID: 18243217
CETP; CVD; HDL; MESA
15.  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.
doi:10.1371/journal.pone.0054018
PMCID: PMC3539988  PMID: 23320117
16.  Prevalence of Traditional Modifiable Cardiovascular Risk Factors in Patients with Rheumatoid Arthritis: Comparison with Control Subjects from the Multi-Ethnic Study of Atherosclerosis 
Objective
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1016/j.semarthrit.2011.07.004
PMCID: PMC3538033  PMID: 22340996
rheumatoid arthritis; cardiovascular risk; epidemiology
17.  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.
doi:10.1159/000333045
PMCID: PMC3225232  PMID: 22056971
Chronic kidney disease; Elderly; Estimated GFR; Kidney decline; Lipoprotein-associated phospholipase A2
18.  Association of Genetic Variants and Incident Coronary Heart Disease in Multi-Ethnic Cohorts. The PAGE Study 
Background
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.
Conclusions
Prospective analyses of white individuals replicated several reported cross-sectional CHD-SNP associations.
doi:10.1161/CIRCGENETICS.111.960096
PMCID: PMC3293207  PMID: 22042884
9p21 locus; incident coronary heart disease; genetic polymorphisms
19.  Longitudinal Changes in Adiponectin and Inflammatory Markers and Relation to Survival in the Oldest Old: The Cardiovascular Health Study All Stars Study 
Background.
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.
Methods.
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).
Results.
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.
Conclusion.
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.
doi:10.1093/gerona/glr098
PMCID: PMC3172562  PMID: 21659339
Adiponectin; C-reactive protein; Interleukin 6; Aging; Mortality
20.  VITAMIN D, PARATHYROID HORMONE, AND CARDIOVASCULAR EVENTS AMONG OLDER ADULTS 
Background
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.
Conclusions
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.
doi:10.1016/j.jacc.2011.03.069
PMCID: PMC3210558  PMID: 21939825
Vitamin D; parathyroid hormone; myocardial infarction; cardiovascular death; heart failure; mortality; mineral metabolism
21.  Inflammation Biomarkers and Risk of All-Cause Mortality in the Reasons for Geographic and Racial Differences in Stroke Cohort 
American Journal of Epidemiology  2011;174(3):284-292.
Inflammation biomarkers, including higher high-sensitivity C-reactive protein (hsCRP) levels, higher white blood cell (WBC) counts, and lower serum albumin levels, are associated with an increased risk of all-cause mortality. Many studies have examined these biomarkers individually, but less is known about their joint association with mortality. hsCRP, WBC count, and serum albumin were measured at baseline in the Reasons for Geographic and Racial Differences in Stroke Study cohort members, who were enrolled in 2003–2007. Over 4.5 years, there were 1,062 deaths in 17,845 participants. High-risk categories were defined as hsCRP or WBC levels above the 75th percentile (5.1 mg/L and 6.9 × 109 cells/L, respectively) and albumin levels below the 25th percentile (4.00 g/dL). The authors derived 4 groups that corresponded to 0 (n = 8,341), 1 (n = 6,277), 2 (n = 2,635), or 3 (n = 592) biomarkers in the high-risk category. After adjustment for age, sex, waist circumference, race, region, smoking, alcohol use, income, educational level, physical activity frequency, and medical history and compared with those with no biomarkers in the high-risk category, the hazard ratios for all-cause mortality for 1, 2, and 3 biomarkers in the high-risk category were 1.56 (95% confidence interval: 1.33, 1.82), 2.19 (95% confidence interval: 1.84, 2.62), and 2.96 (95% confidence interval: 2.30, 3.80), respectively (Ptrend < 0.0001). Adding the 3 inflammation biomarkers to a fully adjusted model improved risk discrimination by 23.7% (95% confidence interval: 9.3, 39.9). Measurement of more than 1 biomarker is more useful in risk prediction than single biomarkers.
doi:10.1093/aje/kwr085
PMCID: PMC3202158  PMID: 21685411
biological markers; cohort studies; C-reactive protein; inflammation; leukocytes; mortality; prospective studies
22.  Association of Serum Phosphate Levels with Aortic Valve Sclerosis and Annular Calcification: the Cardiovascular Health Study 
Objectives
To evaluate mineral metabolism markers as potential risk factors for calcific aortic valve disease.
Background
Mineral metabolism disturbances are common among older people and may contribute to cardiac valvular calcification. Associations of serum mineral metabolism markers with cardiac valvular calcification have not been evaluated in a well-characterized general population of older adults.
Methods
We measured serum levels of phosphate, calcium, parathyroid hormone, and 25-hydroxyvitamin D in 1,938 Cardiovascular Health Study participants who were free of clinical cardiovascular disease and who underwent echocardiography measurements of aortic valve sclerosis (AVS), mitral annular calcification (MAC), and aortic annular calcification (AAC). We used logistic regression models to estimate associations of mineral metabolism markers with AVS, MAC, and AAC after adjustment for relevant confounding variables, including kidney function.
Results
The respective prevalences of AVS, MAC, and AAC were 54%, 39%, and 44%. Each 0.5 mg/dl higher serum phosphate concentration was associated with a greater adjusted odds of AVS (odds ratio 1.17, 95% confidence interval 1.04 to 1.31, p = 0.01), MAC (odds ratio 1.12, 95% confidence interval 1.00 to 1.26, p =0.05), and AAC (odds ratio 1.12, 95% confidence interval 0.99 to 1.25, p = 0.05). In contrast, serum calcium, parathyroid hormone, and 25-hydroxyvitamin D concentrations were not associated with aortic or mitral calcification.
Conclusions
Higher serum phosphate levels within the normal range are associated with valvular and annular calcification in a community-based cohort of older adults. Phosphate may be a novel risk factor for calcific aortic valve disease and warrants further study.
doi:10.1016/j.jacc.2010.11.073
PMCID: PMC3147295  PMID: 21737022
Phosphate; Aortic Valve; Mitral Valve; Calcification; Epidemiology
23.  Racial differences in the association of pentraxin-3 with kidney dysfunction: the Multi-Ethnic Study of Atherosclerosis 
Nephrology Dialysis Transplantation  2010;26(6):1903-1908.
Background. Pentraxin-3 (PTX3), an inflammatory marker thought to be related to vascular inflammation, is elevated in advanced chronic kidney disease (CKD). Whether PTX3 is associated with mild to moderate kidney dysfunction is unknown.
Methods. We tested associations of proteins in the pentraxin family [PTX3, C-reactive protein (CRP) and serum amyloid protein (SAP)] with estimated glomerular filtration rate by cystatin C (eGFRcys) and microalbuminuria among 2824 participants in the Multi-Ethnic Study of Atherosclerosis. Associations were tested using multivariable linear regression with adjustment for demographics (age, gender, annual income), comorbidities (diabetes, hypertension, smoking, body mass index, low-density lipoprotein, high-density lipoprotein, triglycerides, ACE inhibitor and statin use) and systemic inflammation [interleukin-6 (IL-6)].
Results. Among the 2824 participants, mean age was 62 years and mean eGFRcys was 94 mL/min/1.73 m2; 25% were white, 25% Chinese, 25% African-American and 25% Hispanic. Among all participants after full adjustment, higher PTX3 was associated with lower eGFRcys independently of IL-6 (β − 3.0 mL/min/1.73 m2 per unit increase in lnPTX3, P < 0.001). In contrast, CRP and SAP were associated with eGFRcys in demographic adjusted models, but these associations were attenuated after adjustment for comorbidities and IL-6 (lnCRP β − 0.06, P = 0.9; lnSAP β − 0.35, P = 0.7). There was a significant interaction with race/ethnicity (P < 0.001) in the association of PTX3 and eGFRcys. After adjustment for demographics, comorbidities and IL-6, this association was significant in blacks (β − 5.7 mL/min/1.73 m2 per unit increase in lnPTX3, P = 0.002) but not in Hispanics (β − 2.4, P = 0.1), Chinese (β − 0.91, P = 0.5) or whites (β − 0.26, P = 0.9). PTX3 and CRP, but not SAP, had correlations with microalbuminuria in unadjusted models (Spearman coefficients PTX3 0.05, P = 0.005; CRP 0.07, P < 0.001; SAP 0.013, P = 0.5), but these were attenuated after full adjustment.
Conclusions. Endovascular inflammation may be an important mechanism associated with early kidney dysfunction, particularly among blacks. This mechanism appears to be independent of IL-6-regulated pathways.
doi:10.1093/ndt/gfq648
PMCID: PMC3145399  PMID: 21079193
C-reactive protein; estimated glomerular filtration rate by cystatin; pentraxin-3; race/ethnicity; serum amyloid protein
24.  Evaluation of the Metabochip Genotyping Array in African Americans and Implications for Fine Mapping of GWAS-Identified Loci: The PAGE Study 
PLoS ONE  2012;7(4):e35651.
The Metabochip is a custom genotyping array designed for replication and fine mapping of metabolic, cardiovascular, and anthropometric trait loci and includes low frequency variation content identified from the 1000 Genomes Project. It has 196,725 SNPs concentrated in 257 genomic regions. We evaluated the Metabochip in 5,863 African Americans; 89% of all SNPs passed rigorous quality control with a call rate of 99.9%. Two examples illustrate the value of fine mapping with the Metabochip in African-ancestry populations. At CELSR2/PSRC1/SORT1, we found the strongest associated SNP for LDL-C to be rs12740374 (p = 3.5×10−11), a SNP indistinguishable from multiple SNPs in European ancestry samples due to high correlation. Its distinct signal supports functional studies elsewhere suggesting a causal role in LDL-C. At CETP we found rs17231520, with risk allele frequency 0.07 in African Americans, to be associated with HDL-C (p = 7.2×10−36). This variant is very rare in Europeans and not tagged in common GWAS arrays, but was identified as associated with HDL-C in African Americans in a single-gene study. Our results, one narrowing the risk interval and the other revealing an associated variant not found in Europeans, demonstrate the advantages of high-density genotyping of common and rare variation for fine mapping of trait loci in African American samples.
doi:10.1371/journal.pone.0035651
PMCID: PMC3335090  PMID: 22539988
25.  Leukocyte Telomere Length and Mortality in the Cardiovascular Health Study 
Background.
Leukocyte telomere length (LTL) is related to diseases of aging, but studies of mortality have been inconsistent.
Methods.
We evaluated LTL in relation to total mortality and specific cause of death in 1,136 participants of the Cardiovascular Health Study who provided blood samples in 1992–1993 and survived through 1997–1998. LTL was measured by Southern blots of the terminal restriction fragments. Cause of death was classified by a committee of physicians reviewing death certificates, medical records, and informant interviews.
Results.
A total of 468 (41.2%) deaths occurred over 6.1 years of follow-up in participants with mean age of 73.9 years (SD 4.7), 65.4% female, and 14.8% African American. Although increased age and male gender were associated with shorter LTLs, African Americans had significantly longer LTLs independent of age and sex (p < .001). Adjusted for age, sex, and race, persons with the shortest quartile of LTL were 60% more likely to die during follow-up than those within the longest quartile (hazard ratio: 1.61, 95% confidence interval: 1.22–2.12, p = .001). The association remained after adjustment for cardiovascular disease risk factors. Evaluations of cause of death found LTL to be related to deaths due to an infectious disease etiology (hazard ratio: 2.80, 95% confidence interval: 1.32–5.94, p = .007), whereas a borderline association was found for cardiac deaths (hazard ratio: 1.82, 95% confidence interval: 0.95–3.49, p = .07) in adjusted models. Risk estimates for deaths due to cancer, dementia, and ischemic stroke were not significant.
Conclusion.
These data weakly corroborate prior findings of associations between LTL and mortality in the elderly.
doi:10.1093/gerona/glq224
PMCID: PMC3055278  PMID: 21289018
Telomere; Mortality; Cause of death; Cardiovascular disease; Heart failure

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