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Translating our knowledge of the biological aging from animal models to humans may give rise to novel approaches of targeting multiple aging-related diseases simultaneously and increasing health span. Here, for the first time, we use transcriptomic signatures of monocytes to identify biological aging pathways underlying multiple aging-related diseases in humans. The ordinal logistic regression was used to cross-sectionally investigate transcriptomics of the comorbidity index in 1264 community-based Multi-Ethnic Study of Atherosclerosis (MESA) adults, 47% Caucasian, 32% Hispanic, 21% African American, and 51% female, aged 55-94 years. The comorbidity index was defined as the number of prevalent aging-related diseases including cardiovascular disease, type-2 diabetes, hypertension, cancer, dementia, chronic kidney disease, chronic obstructive pulmonary disease, and hip fracture. We identified 708 gene transcripts associated with the comorbidity index (FDR < 0.05) after adjusting for age, sex, ethnicity, and study site. In a weighted gene co-expression network analysis, as postulated, aging-related declines in apoptosis/autophagy (OR = 1.21 per SD increment, p = 0.0006) and ribosome/mitochondrion (OR = 0.90 per SD increment, p = 0.05) were positively associated with the comorbidity index. After adjusting for multiple comparisons, we identified 10 comorbidity-associated modules (FDR < 0.05), including the module of apoptosis/autophagy. There were three inter-correlated modules of these 10 involved in the complement subcomponent C1q, Fc gamma receptor I, and Fc gamma receptor III of the immune system, respectively. Aging-related upregulation of these three modules was positively associated with the comorbidity index. The odds of comorbidity increased with more of these modules acting together in a dose-response fashion. In conclusion, transcriptomic analysis of human immune cells may identify biomarker panels indicative of comprehensive biological mechanisms, especially immune signaling pathways, contributing to health aging., (© 2022. The Author(s), under exclusive licence to American Aging Association.)

Background: Level of alcohol consumption is associated with differential risk of atherosclerosis, but little research has investigated this association among HIV+ persons. We evaluated the association between long-term alcohol use and incident atherosclerosis among HIV+ persons., Methods: We utilized data from HIV+ participants of the Women's Interagency HIV Study (n=483) and the Multicenter AIDS Cohort Study (n=305) without history of cardiovascular disease. Atherosclerosis was assessed two times by B-mode carotid artery ultrasound imaging from 2004 to 2013. Presence of plaque was defined as focal carotid intima-media thickness over 1.5mm. Those with no plaque at baseline and plaque at follow-up were considered incident cases of atherosclerosis. Group-based trajectory models were used to categorize participants into 10-year drinking patterns representing heavy, moderate, or abstinent-low. Multivariable logistic regressions were conducted to assess the association of long-term moderate and heavy use on atherosclerosis, compared to abstinent-low., Results: Heavy alcohol consumption was not statistically significantly associated with risk for incident atherosclerosis in women (AOR 1.10, CI 0.40-3.02) or men (AOR 1.31, CI 0.43-4.00), compared to abstinence-low. Moderate consumption was associated with 54% lower odds for incident disease in men (AOR 0.46, CI 0.21-1.00), but not in women (AOR 1.08, CI 0.58-2.00). In cohort-combined analyses, alcohol consumption was not statistically significantly association with incident atherosclerosis (moderate AOR 0.78, CI 0.48-1.27; heavy AOR 1.33, CI 0.66-2.69)., Conclusion: Moderate alcohol consumption was associated with a significant protective effect on incident atherosclerosis in men only. No other levels of alcohol consumption significantly predicted atherosclerosis in men and women compared to abstinent-low., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Little is known regarding the epigenetic basis of atherosclerosis. Here we present the CD14+ blood monocyte transcriptome and epigenome signatures associated with human atherosclerosis. The transcriptome signature includes transcription coactivator, ARID5B, which is known to form a chromatin derepressor complex with a histone H3K9Me2-specific demethylase and promote adipogenesis and smooth muscle development. ARID5B CpG (cg25953130) methylation is inversely associated with both ARID5B expression and atherosclerosis, consistent with this CpG residing in an ARID5B enhancer region, based on chromatin capture and histone marks data. Mediation analysis supports assumptions that ARID5B expression mediates effects of cg25953130 methylation and several cardiovascular disease risk factors on atherosclerotic burden. In lipopolysaccharide-stimulated human THP1 monocytes, ARID5B knockdown reduced expression of genes involved in atherosclerosis-related inflammatory and lipid metabolism pathways, and inhibited cell migration and phagocytosis. These data suggest that ARID5B expression, possibly regulated by an epigenetically controlled enhancer, promotes atherosclerosis by dysregulating immunometabolism towards a chronic inflammatory phenotype.The molecular mechanisms mediating the impact of environmental factors in atherosclerosis are unclear. Here, the authors examine CD14+ blood monocyte's transcriptome and epigenome signatures to find differential methylation and expression of ARID5B to be associated with human atherosclerosis.

Background: In the USA, ethnic disparities in atherosclerosis persist after accounting for known risk factors. Ambient air pollution is associated with increased levels of atherosclerosis and differs in the USA by race/ethnicity. We estimated the influence of ambient air pollution exposure to ethnic differences in common carotid intima-media thickness (IMT)., Methods: We cross-sectionally studied 6347 Caucasian-American, African-American, Hispanic and Chinese adults across 6 US cities in 2000-2002. Annual ambient air pollution concentrations (fine particulate matter [PM2.5] and oxides of nitrogen [NOX]) were estimated at each participant's residence. IMT was assessed by ultrasound., Results: The mean IMT was 19.4 and 37.6 μm smaller for Hispanic women and men, 53.6 and 7.1 μm smaller for Chinese women and men, and 23.4 and 38.7 μm higher for African-American women and men compared with Caucasian-American women and men. After adjustment for PM2.5, the differences in IMT remained similar for Hispanic and African-American participants but was even more negative for Chinese participants (mean IMT difference of -58.4 μm for women and -15.7 μm for men) compared with Caucasian-American participants. The IMT difference in Chinese participants compared with Caucasian-American participants related to their higher PM2.5 exposures was 4.8 μm (95% CI 0.2 to 10.8) for women and 8.6 μm (95% CI 3.4 to 15.3) for men. NOX was not related to ethnic differences in IMT., Conclusions: The smaller carotid IMT levels in Chinese participants were even smaller after accounting for higher PM2.5 concentrations in Chinese participants compared with Caucasian-American participants. Air pollution was not related to IMT differences in African-American and Hispanic participants compared with Caucasian-American participants., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background and Purpose: Low vitamin D levels, measured by serum 25-hydroxyvitamin D [25(OH)D], are associated with increased stroke risk. Less is known about whether this association differs by race or D binding protein (DBP) single nucleotide polymorphism (SNP) status. Our objective was to characterize the associations of and interactions between 25(OH)D levels and DBP SNPs with incident stroke. It was hypothesized that associations of low 25(OH)D with stroke risk would be stronger amongst persons with genotypes associated with higher DBP levels., Methods: 25(OH)D was measured by mass spectroscopy in 12 158 participants in the Atherosclerosis Risk in Communities (ARIC) study (baseline 1990-1992, mean age 57 years, 57% female, 23% black) and they were followed through 2011 for adjudicated stroke events. Two DBP SNPs (rs7041, rs4588) were genotyped. Cox models were adjusted for demographic/behavioral/socioeconomic factors., Results: During a median of 20 years follow-up, 804 incident strokes occurred. The lowest quintile of 25(OH)D (<17.2 ng/ml) was associated with higher stroke risk [hazard ratio (HR) 1.34 (1.06-1.71) versus highest quintile]; this association was similar by race (P interaction 0.60). There was weak evidence of increased risk of stroke amongst those with 25(OH)D < 17.2 ng/ml and either rs7041 TG/GG [HR = 1.29 (1.00-1.67)] versus TT genotype [HR = 1.19 (0.94-1.52)] (P interaction 0.28) or rs4588 CA/AA [HR = 1.37 (1.07-1.74)] versus CC genotype [HR = 1.14 (0.91-1.41)] (P interaction 0.11)., Conclusions: Low 25(OH)D is a risk factor for stroke. Persons with low 25(OH)D who are genetically predisposed to high DBP (rs7041 G, rs4588 A alleles), who therefore have lower predicted bioavailable 25(OH)D, may be at greater risk for stroke, although our results were not conclusive and should be interpreted as hypothesis generating., (© 2015 EAN.)

Objective: Heart failure (HF) is a leading cause of mortality especially in older populations. Early detection of high-risk individuals is imperative for primary prevention. The purpose of this study was to develop a HF risk model from a population without clinical cardiac disease., Methods: The Multi-Ethnic Study of Atherosclerosis is a multicentre observational cohort study following 6814 subjects (mean age 62±10 years; 47% men) who were free of clinical cardiovascular disease at baseline. Median follow-up was 4.7 years. HF events developed in 176 participants. Cox proportional hazards models and regression coefficients were used to determine independent risk factors and generate a 5-year risk score for incident HF. Bootstrapping with bias correction was used for internal validation., Results: Independent predictors for HF (HR, p value) were age (1.30 (1.10 to 1.50) per 10 years), male gender (2.27 (1.53 to 3.36)), current smoking (1.97 (1.15 to 3.36)), body mass index (1.40 (1.10 to 1.80) per 5 kg/m(2)), systolic blood pressure (1.10 (1.00 to 1.10) per 10 mm Hg), heart rate (1.30) (1.10 to 1.40) per 10 bpm), diabetes (2.27 (1.48 to 3.47)), N-terminal pro-B-type natriuretic peptide (NT proBNP) (2.48 (2.16 to 2.84) per unit log increment) and left ventricular mass index (1.40 (1.30 to 1.40) per 10 g/m(2)). A parsimonious model based on age, gender, body mass index, smoking status, systolic blood pressure, heart rate, diabetes and NT proBNP natriuretic peptide predicted incident HF risk with a c-statistic of 0.87., Conclusions: A clinical algorithm based on risk factors readily available in the primary care setting can used to identify individuals with high likelihood of developing HF without pre-existing cardiac disease., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Importance: Vitamin D deficiency has been associated with hypertension, diabetes mellitus, and incident stroke. Little is known about the association between vitamin D and subclinical cerebrovascular disease., Objective: To examine the relationship of 25-hydroxyvitamin D (25[OH]D) levels with cerebrovascular abnormalities as assessed on brain magnetic resonance imaging (MRI) among participants of the Atherosclerosis Risk in Communities (ARIC) Brain MRI study., Design, Setting, and Participants: Participants were white and black adults aged 55 to 72 years with no history of clinical stroke who underwent a cerebral MRI at ARIC visit 3 (n = 1622) and a second cerebral MRI approximately 10 years later (n = 888)., Exposures: The 25(OH)D level was measured by mass spectrometry at visit 3, with levels adjusted for calendar month and categorized using race-specific quartiles., Main Outcomes and Measures: The cross-sectional and prospective associations of 25(OH)D levels with white matter hyperintensities (WMHs) and MRI-defined infarcts were investigated using multivariable regression models., Results: The mean age of the participants was 62 years, 59.6% were women, and 48.6% were black. Lower 25(OH)D levels were not significantly associated with WMH score of severity, prevalent high-grade WMH score (≥3), or prevalent infarcts in cross-sectional, multivariable-adjusted models (all P > .05). Similarly, no significant prospective associations were found for lower 25(OH)D levels with change in WMH volume, incident high WMH score (≥3), or incident infarcts on the follow-up MRI, which occurred approximately 10 years later., Conclusions and Relevance: A single measure of 25(OH)D was not cross-sectionally associated with WMH grade or prevalent subclinical infarcts and was not prospectively associated with WMH progression or subclinical brain infarcts seen on serial cerebral MRIs obtained approximately 10 years apart. These findings do not support optimizing vitamin D levels for brain health.

Backgrounds: QT is a risk factor for sudden cardiac death (SCD). A genome-wide association study identified NOS1AP variants associated with QT, which have been replicated in predominantly Caucasian (CAU) populations. We used the Multi-Ethnic Study of Atherosclerosis to examine association of QT with NOS1AP variants in an ethnically diverse cohort., Methods: Twenty-eight tagging SNPs spanning NOS1AP were genotyped in 2847 MESA participants (approximately equal numbers of CAU, African Americans (AFA), Hispanics (HIS), and Chinese (CHN)), age 45-84 years, without cardiovascular disease. QT was measured using 12-lead ECG. Associations between QT and NOS1AP variants were evaluated using linear regression, adjusted for heart rate, age, gender, and field center stratified by ancestry, using an additive inheritance model. Ancestry informative markers (AIMs) and principal components using AIMs were used as additional covariates., Results: More NOS1AP SNPs were associated with QT in CAU than the other races. In CAU, each copy of rs1932933 risk allele was associated with an increase in QT (4.9 msec, P = 7.20 × 10-7). Significant associations in CAU and HIS were located at the 5' end, while associations in CHN were located at the 3' end., Conclusions: NOS1AP variants were associated with QT in CAU, with weaker evidence for selected variants in HIS and CHN. Location of significant SNPs varied across ancestry. We identified possible novel associations at the 3' end of NOS1AP, where we observed significant association with QT in CHN only. Genotyping within these regions may determine functional variants affecting QT and SCD risk. In addition, investigations are needed across ethnically diverse population cohorts., (©2013 Wiley Periodicals, Inc.)

Objective: We previously reported a statistically significant association of SCARB1 intronic single nucleotide polymorphism (SNP) rs10846744 with common carotid intimal-medial artery thickness in each of the 4 Multi-Ethnic Study of Atherosclerosis racial/ethnic groups (white, Chinese, black, and Hispanic)., Methods and Results: Using an expanded sample of 7936 Multi-Ethnic Study of Atherosclerosis participants, phenotyped for measures of subclinical atherosclerosis, incident myocardial infarction, and cardiovascular disease, and genotyped through the SNP Health Association Resource project, we have now examined the genetic association of these phenotypes with 126 genotyped and imputed SCARB1 SNPs. We also performed stratified analyses to examine whether SCARB1 SNP effects differed by sex. Our analysis of the full Multi-Ethnic Study of Atherosclerosis cohort provides strong evidence for the association of rs10846744 with common carotid intimal-medial thickness (P=1.04E-4 in combined analysis of all 4 Multi-Ethnic Study of Atherosclerosis racial/ethnic groups). In sex-stratified analysis, we observed statistically significant association of rs10846744 with incident cardiovascular disease events in males (P=0.01). Examining analytical results from the Myocardial Infarction Genetics Consortium for replication, we observed further support for the association of rs10846744 with myocardial infarction., Conclusions: The SCARB1 SNP, rs10846744, exerts a major effect on subclinical atherosclerosis and incident cardiovascular disease in humans.

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., (Copyright © 2012. Published by Elsevier Inc.)

Background: Cardiovascular disease is one of the major causes of death in systemic lupus erythematosus (SLE). A study was undertaken to investigate whether treatment with statins would reduce subclinical measures of atherosclerosis over a 2-year period., Methods: 200 patients with SLE without clinical cardiovascular disease were randomised to receive atorvastatin 40 mg daily or an identical placebo. At baseline and after 2 years of follow-up, helical CT scanning (for coronary artery calcium) and carotid duplex (for intima media thickness/plaque) were performed. Patients were seen for measures of disease activity at 1 month, 3 months and quarterly thereafter. The primary outcome variable was change in coronary artery calcium., Results: At baseline, 43% had coronary artery calcium. At 2 years there was no significant difference between the groups in progression of coronary artery calcium, carotid intima media thickness or carotid plaque. There was no significant difference between the groups in disease activity, measures of inflammation or endothelial cell activation., Conclusion: This study provides no evidence that atorvastatin reduces subclinical measures of atherosclerosis or disease activity over 2 years in patients with SLE. In fact, it does not appear to reduce biochemical measures of inflammation. The anti-inflammatory effects of statins observed in the general population were not replicated in this SLE clinical trial. Clinicaltrials.gov (NCT 00120887).

Increased left ventricular (LV) mass and changes in LV geometry may precede hypertension onset. The authors examined the associations of LV mass and geometry, assessed by cardiac magnetic resonance imaging, with hypertension incidence in 2,567 normotensive participants enrolled in 2000-2002 in the Multi-Ethnic Study of Atherosclerosis, an ethnically diverse, population-based, US study. Over a median follow-up of 4.8 years, 745 (29%) participants developed hypertension. In a fully adjusted model including baseline blood pressure, the relative risks of incident hypertension from the lowest to highest LV mass quartile were 1.00 (referent), 1.13 (95% confidence interval (CI): 0.89, 1.43), 1.28 (95% CI: 1.00, 1.63), and 1.78 (95% CI: 1.38, 2.30) (P < 0.001 for linear trend). Higher levels of LV concentric geometry, defined by higher LV mass to end-diastolic volume quartiles, were associated with higher risk of incident hypertension in a fully adjusted model (P = 0.044 for linear trend). In a final model containing both quartiles of LV mass and LV mass/volume along with all covariates including baseline blood pressure, higher LV mass quartiles were associated with incident hypertension (P < 0.001 for linear trend), whereas higher LV mass/volume quartiles were not (P = 0.643 for linear trend). In this multiethnic cohort, alterations in LV mass preceded hypertension onset among normotensive individuals.

Background: Atherosclerosis is the leading cause of cardiovascular disease (CVD). Traditional risk factors can be used to identify individuals at high risk for developing CVD and are generally associated with the extent of atherosclerosis; however, substantial numbers of individuals at low or intermediate risk still develop atherosclerosis., Results: A case-control study was performed using microarray gene expression profiling of peripheral blood from 119 healthy women in the Multi-Ethnic Study of Atherosclerosis cohort aged 50 or above. All participants had low (<10%) to intermediate (10% to 20%) predicted Framingham risk; cases (N = 48) had coronary artery calcium (CAC) score >100 and carotid intima-media thickness (IMT) >1.0 mm, whereas controls (N = 71) had CAC<10 and IMT <0.65 mm. We identified two major expression profiles significantly associated with significant atherosclerosis (odds ratio 4.85; P<0.001); among those with Framingham risk score <10%, the odds ratio was 5.30 (P<0.001). Ontology analysis of the gene signature reveals activation of a major innate immune pathway, toll-like receptors and IL-1R signaling, in individuals with significant atherosclerosis., Conclusion: Gene expression profiles of peripheral blood may be a useful tool to identify individuals with significant burden of atherosclerosis, even among those with low predicted risk by clinical factors. Furthermore, our data suggest an intimate connection between atherosclerosis and the innate immune system and inflammation via TLR signaling in lower risk individuals.

Objective: The goal of this study was to compare and contrast coronary artery calcium (CAC) with abdominal aortic calcium (AAC) in terms of their associations with traditional and novel cardiovascular disease (CVD) risk factors., Methods and Results: We measured both AAC and CAC using computed tomography scans in 1974 men and women aged 45 to 84 years from a multiethnic cohort. Traditional and novel CVD risk factors were examined separately in relation to AAC and CAC, using logistic regression for qualitative categorical comparisons and multiple linear regression for quantitative continuous comparisons. AAC was significantly associated with cigarette smoking and dyslipidemia and showed no gender difference. In contrast, CAC showed much weaker associations with smoking and dyslipidemia and a strong male predominance. Age and hypertension were associated similarly and significantly with AAC and CAC. Novel risk factors generally showed no independent association with either calcium measure, although in subset analyses, phosphorus, but not calcium, was related to CAC. The receiver operating characteristic curves for the qualitative results and the r(2) values for the quantitative analyses were both much higher for AAC than for CAC., Conclusions: AAC showed stronger correlations with most CVD risk factors than did CAC. The predictive value of AAC compared with CAC for incident CVD events remains to be evaluated.

Background: We hypothesized that serum magnesium (Mg) is associated with increased risk of sudden cardiac death (SCD)., Methods: The Atherosclerosis Risk in Communities Study assessed risk factors and levels of serum Mg in a cohort of 45- to 64-year-old subjects in 1987-1989 (n = 14,232). After an average of 12 years of follow-up, we observed 264 cases of SCD, as determined by physician review of all suspected cases. We used proportional hazards regression to evaluate the association of serum Mg with risk of SCD., Results: Individuals in the highest quartile of serum Mg were at significantly lower risk of SCD in all models. This association persisted after adjustment for potential confounding variables, with an almost 40% reduced risk of SCD (hazard ratio 0.62, 95% CI 0.42-0.93) in quartile 4 versus 1 of serum Mg observed in the fully adjusted model., Conclusions: This study suggests that low levels of serum Mg may be an important predictor of SCD. Further research into the effectiveness of Mg supplementation for those considered to be at high risk for SCD is warranted., (2010 Mosby, Inc. All rights reserved.)

The MESA (Multi-Ethnic Study of Atherosclerosis) is an ongoing study of the prevalence, risk factors, and progression of subclinical cardiovascular disease in a multi-ethnic cohort. It provides a valuable opportunity to examine the development and progression of CAC (coronary artery calcium), which is an important risk factor for the development of coronary heart disease. In MESA, about half of the CAC scores are zero and the rest are continuously distributed. Such data has been referred to as "zero-inflated data" and may be described using two-part models. Existing two-part model studies have limitations in that they usually consider parametric models only, make the assumption of known forms of the covariate effects, and focus only on the estimation property of the models. In this article, we investigate statistical modeling of CAC in MESA. Building on existing studies, we focus on two-part models. We investigate both parametric and semiparametric, and both proportional and nonproportional models. For various models, we study their estimation as well as prediction properties. We show that, to fully describe the relationship between covariates and CAC development, the semiparametric model with nonproportional covariate effects is needed. In contrast, for the purpose of prediction, the parametric model with proportional covariate effects is sufficient. This study provides a statistical basis for describing the behaviors of CAC and insights into its biological mechanisms.

Objective: Cardiovascular (CV) morbidity and mortality are increased in rheumatoid arthritis (RA). Prior investigations of the association of RA with measures of carotid atherosclerosis have yielded conflicting results. We compared carotid intima-media thickness (IMT) of both the common carotid (CCA) and proximal internal carotid (bulb-ICA) arteries, and plaque prevalence, between RA and non-RA participants., Methods: Subjects with RA were participants in a cohort study of subclinical CV disease in RA. Non-RA controls were selected from the Multi-Ethnic Study of Atherosclerosis. Both groups underwent B-mode ultrasonography of the right and left CCA and bulb-ICA. Linear regression was used to model the association of RA status with CCA and bulb-ICA-IMT, and logistic regression for the association of RA status with plaque., Results: We compared 195 RA patients to 198 non-RA controls. CV risk factors were similarly distributed, except for a higher prevalence of hypertension in the RA group. Mean adjusted bulb-ICA-IMT was higher in RA patients than controls (1.16 vs 1.02 mm, respectively; p < 0.001), while mean adjusted CCA-IMT did not differ significantly. After adjusting for CV risk factors, the odds of plaque were significantly increased in RA participants compared to controls (OR 2.41, 95% CI 1.26-4.61). The association of gender, age, smoking, and hypertension with bulb-ICA-IMT and plaque did not significantly differ by RA status. Interleukin 6 was strongly associated with bulb-ICA-IMT and plaque in controls but not in RA patients. In the RA group, shared epitope was associated with an increased prevalence of plaque., Conclusion: Compared to controls, RA was associated with a higher prevalence and higher severity of atherosclerosis in the bulb-ICA but not the CCA. Our data suggest that future studies in RA that utilize carotid artery measurements should include assessment of the bulb-ICA.

Aims/hypothesis: To validate the reported association between rs10494366 in NOS1AP (the gene encoding nitric oxide synthase-1 adaptor protein) and the incidence of type 2 diabetes in calcium channel blocker (CCB) users and to identify additional NOS1AP variants associated with type 2 diabetes risk., Methods: Data from 9 years of follow-up in 9,221 middle-aged white and 2,724 African-American adults free of diabetes at baseline from the Atherosclerosis Risk in Communities study were analysed. Nineteen NOS1AP variants were examined for associations with incident diabetes and fasting glucose levels stratified by baseline CCB use., Results: Prevalence of CCB use at baseline was 2.7% (n = 247) in whites and 2.3% (n = 72) in African-Americans. Among white CCB users, the G allele of rs10494366 was associated with lower diabetes incidence (HR 0.57, 95% CI 0.35-0.92, p = 0.016). The association was marginally significant after adjusting for age, sex, obesity, smoking, alcohol use, physical activity, hypertension, heart rate and electrocardiographic QT interval (HR 0.63, 95% CI 0.38-1.04, p = 0.052). rs10494366 was associated with lower average fasting glucose during follow-up (p = 0.037). No other variants were associated with diabetes risk in CCB users after multiple-testing correction. No associations were observed between any NOS1AP variant and diabetes development in non-CCB users. NOS1AP variants were not associated with diabetes risk in either African-American CCB users or non-CCB users., Conclusions/interpretation: We have independently replicated the association between rs10494366 in NOS1AP and incident diabetes among white CCB users. Further exploration of NOS1AP variants and type 2 diabetes and functional studies of NOS1AP in type 2 diabetes pathology is warranted.

Background: Little is known about the association of scavenger receptor class B type I (SCARB1) single-nucleotide polymorphisms (SNPs) and subclinical atherosclerosis, particularly in subjects of different racial/ethnic backgrounds. We examined this relationship in the Multi-Ethnic Study of Atherosclerosis., Methods and Results: Forty-three SCARB1-tagging SNPs were genotyped. Baseline examinations included fasting lipids and subclinical atherosclerosis phenotypes (coronary artery calcification, common carotid intimal-medial artery thickness [CCIMT], and internal carotid intimal-medial artery thickness). Examining SNP associations with different subclinical atherosclerosis phenotypes across multiple racial/ethnic groups with adjustment for multiple covariates, we found that the C allele of SNP rs10846744 was associated with higher CCIMT in African American (P=0.03), Chinese (P=0.02), European American (P=0.05), and Hispanic participants (P=0.03) and was strongly associated in pooled analyses (P=0.0002). The results also showed that the association of this SNP with CCIMT was independent of lipids and other well-established cardiovascular risk factors. Stratifying by sex, there seemed to be a strong association of rs10846744 with CCIMT in women, but no genotype-sex interactions were observed., Conclusions: Variation in SCARB1 at rs10846744 was significantly associated with CCIMT across racial/ethnic groups in Multi-Ethnic Study of Atherosclerosis.

Background: Many different genetic and clinical factors have been identified as causes or contributors to atherosclerosis. We present a model of preclinical atherosclerosis based on genetic and clinical data that predicts the presence of coronary artery calcification in healthy Americans of European descent 45 to 84 years of age in the Multi-Ethnic Study of Atherosclerosis (MESA)., Methods and Results: We assessed 712 individuals for the presence or absence of coronary artery calcification and assessed their genotypes for 2882 single-nucleotide polymorphisms. With the use of these single-nucleotide polymorphisms and relevant clinical data, a Bayesian network that predicts the presence of coronary calcification was constructed. The model contained 13 single-nucleotide polymorphisms (from genes AGTR1, ALOX15, INSR, PRKAB1, IL1R2, ESR2, KCNK1, FBLN5, PPARA, VEGFA, PON1, TDRD6, PLA2G7, and 1 ancestry informative marker) and 5 clinical variables (sex, age, weight, smoking, and diabetes mellitus) and achieved 85% predictive accuracy, as measured by area under the receiver operating characteristic curve. This is a significant (P<0.001) improvement on models that use just the single-nucleotide polymorphism data or just the clinical variables., Conclusions: We present an investigation of joint genetic and clinical factors associated with atherosclerosis that shows predictive results for both cases, as well as enhanced performance for their combination.

Background: Although brachial artery flow-mediated dilation (FMD) predicts recurrent cardiovascular events, its predictive value for incident cardiovascular disease (CVD) events in adults free of CVD is not well established. We assessed the predictive value of FMD for incident CVD events in the Multi-Ethnic Study of Atherosclerosis (MESA)., Methods and Results: Brachial artery FMD was measured in a nested case-cohort sample of 3026 of 6814 subjects (mean+/-SD age, 61.2+/-9.9 years) in MESA, a population-based cohort study of adults free of clinical CVD at baseline recruited at 6 clinic sites in the United States. The sample included 50.2% female, 34.3% white, 19.7% Chinese, 20.8% black, and 25.1% Hispanic subjects. Probability-weighted Cox proportional hazards analysis was used to examine the association between FMD and 5 years of adjudicated incident CVD events, including incident myocardial infarction, definite angina, coronary revascularization (coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, or other revascularization), stroke, resuscitated cardiac arrest, and CVD death. Mean (SD) FMD of the cohort was 4.4% (2.8). In probability-weighted Cox models, FMD/unit SD was significantly associated with incident cardiovascular events in the univariate model (adjusted for age and sex) (hazard ratio, 0.79; 95% confidence interval, 0.65 to 0.97; P=0.01), after adjustment for the Framingham Risk Score (FRS) (hazard ratio, 0.80; 95% confidence interval, 0.62 to 0.97; P=0.025), and in the multivariable model (hazard ratio, 0.84; 95% confidence interval, 0.71 to 0.99; P=0.04) after adjustment for age, sex, diabetes mellitus, cigarette smoking status, systolic blood pressure, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, heart rate, statin use, and blood pressure medication use. The c statistic (area under the curve) values of FMD, FRS, and FRS+FMD were 0.65, 0.74, and 0.74, respectively. Compared with the FRS alone, the addition of FMD to the FRS net correctly reclassifies 52% of subjects with no incident CVD event but net incorrectly reclassifies 23% of subjects with an incident CVD event, an overall net correct reclassification of 29% (P<0.001)., Conclusions: Brachial FMD is a predictor of incident cardiovascular events in population-based adults. Even though the addition of FMD to the FRS did not improve discrimination of subjects at risk of CVD events in receiver operating characteristic analysis, it improved the classification of subjects as low, intermediate, and high CVD risk compared with the FRS.

HMG-CoA reductase (HMGCR) is an enzyme involved in cholesterol synthesis. To investigate the contribution of the HMGCR gene to lipids and lipoprotein subfractions in different ethnicities, we performed an association study in the Multi-Ethnic Study of Atherosclerosis (MESA). In total, 2,444 MESA subjects [597 African-Americans (AA), 627 Chinese-Americans (CHA), 612 European-Americans (EA), and 608 Hispanic-Americans (HA)] without statin use were included. Participants had measurements of blood pressure, anthropometry, and fasting blood samples. Subjects were genotyped for 10 single nucleotide polymorphisms (SNPs). After excluding SNPs with minor allele frequency <5%, a single block was constructed. The most frequent haplotype was H1 (41-56%) in all ethnic groups except AA (H2a, 44.9%). Lower triglyceride level was associated with the H2a haplotype in AA and H2 in HA. In HA, H4 carriers had higher levels of triglyceride and small low-density lipoprotein (s-LDL), and lower high-density lipoprotein cholesterol (HDL-c), while carriers with H7 or H8 had associations with these traits in the opposite direction. No significant association was discovered in both CHA and EA. The total variation for triglyceride that could be explained by H2 alone was 2.6% in HA and 1.4% in AA. In conclusion, HMGCR gene variation is associated with multiple lipid/lipoprotein traits, especially with triglyceride, s-LDL, and HDL-c. The impact of the genetic variance is modest and differs greatly among ethnicities.

Coronary artery calcium (CAC), carotid intima-media thickness (CIMT), and reduced ankle brachial indices (ABI) are markers of subclinical vascular disease strongly associated with aging. The authors identified factors associated with low levels of subclinical vascular disease in 1824 participants 70 years and older in the Multi-Ethnic Study of Atherosclerosis. A total of 452 had low CAC (<25th percentile), 441 had low CIMT (<25th percentile), 1636 had normal ABI (>0.9), and 165 had a combination index indicating favorable values for all 3 parameters. This combination index was independently associated with younger age (odds ratio [OR] 2.5 per 1 SD [95% confidence interval (CI), 1.8-3.6]), female sex (OR 3.0 [95% CI, 1.9-4.8]), lower body mass index (OR 1.6 per 1 SD [95% CI, 1.2-2.0]), absence of hypertension (OR 1.8 [95% CI, 1.2-2.6]), absence of dyslipidemia (OR 1.6 [95% CI, 1.04-2.4]), and never-smoking (OR 1.7 [95% CI, 1.1-2.6]). No significant associations were observed for C-reactive protein, education, diet, or physical activity. Favorable levels of multiple traditional risk factors, but not several novel risk factors, were associated with subclinical markers of successful cardiovascular aging., ((c) 2009 Wiley Periodicals, Inc.)

Background: ATP-binding cassette A1 (ABCA1) and cholesteryl ester transfer protein (CETP) play important roles in the reverse cholesterol transport pathway. The associations of ABCA1 and CETP polymorphisms with lipoprotein subclasses have not been extensively studied., Methods: We genotyped 2 ABCA1 and 5 CETP polymorphisms in 999 participants of the Multi-Ethnic Study of Atherosclerosis (MESA) and studied their associations with HDL and LDL subclass particle concentrations, measured by nuclear magnetic resonance spectroscopy., Results: ABCA1 and CETP polymorphisms were associated with different and distinct changes in lipoprotein subclass concentrations. The ABCA1 1051G/A AA genotype, previously found to be associated with cardioprotective effects in this cohort, was associated with a 5.5% higher concentration of small HDL particles (P = 0.024). The CETP TaqIB B2B2, -2505C/A AA, and -629C/A AA genotypes, previously demonstrated to lack cardioprotective effects, were associated with 15.2%, 15.4%, and 11.7% higher HDL cholesterol concentrations, respectively, and 36.5%, 40.7%, and 25.4% higher large HDL particle concentrations (P < 0.0001). The minor alleles of the A373P and R451Q polymorphisms were associated with lower large HDL particle concentrations., Conclusions: Our study of the influence of ABCA1 and CETP genetic variants on lipoprotein subclasses demonstrates the importance of interpreting lipoprotein subclasses within the context of the biochemical processes involved in the alterations. In the case of HDL, the study of subclass particle numbers and sizes may not be sufficiently informative. Assays for HDL function may be needed to supplement quantification of HDL cholesterol and HDL particle numbers and sizes.

The cholesteryl ester transfer 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, carotid intimal-medial thickness (IMT), and carotid artery plaque measured by ultrasonography. Carriers of the 451Q and 373P alleles have a 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). Polymorphism is associated with neither common nor 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.

Background and purpose Some recent studies in older, largely white populations suggest that vitamin D, measured by 25-hydroxyvitamin D [25( OH)D], is important for cognition, but such results may be affected by reverse causation. Measuring 25( OH)D in late middle age before poor cognition affects behavior may provide clearer results. Methods This was a prospective cohort analysis of 1652 participants (52% white, 48% black) in the Atherosclerosis Risk in Communities ( ARIC) Brain MRI Study. 25( OH)D was measured from serum collected in 1993-1995. Cognition was measured by the delayed word recall test ( DWRT), the digit symbol substitution test ( DSST) and the word fluency test ( WFT). Dementia hospitalization was defined by ICD-9 codes. Adjusted linear, logistic and Cox proportional hazards models were used. Results Mean age of participants was 62 years and 60% were female. Mean 25( OH)D was higher in whites than blacks (25.5 vs. 17.3 ng/ml, P < 0.001). Lower 25( OH)D was not associated with lower baseline scores or with greater DWRT, DSST or WFT decline over a median of 3 or 10 years of follow-up ( P > 0.05). Over a median of 16.6 years, there were 145 incident hospitalized dementia cases. Although not statistically significant, lower levels of 25( OH)D were suggestive of an association with increased dementia risk [hazard ratio for lowest versus highest race-specific tertile: whites 1.32 (95% confidence interval 0.69, 2.55); blacks 1.53 (95% confidence interval 0.84, 2.79)]. Conclusions In contrast to prior studies performed in older white populations, our study of late middle age white and black participants did not find significant associations between lower levels of 25( OH)D with lower cognitive test scores at baseline, change in scores over time or dementia risk. [ABSTRACT FROM AUTHOR]