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1.  Vitamin D and Cognitive Function and Dementia Risk in a Biracial Cohort: the ARIC Brain MRI Study 
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.
Prospective cohort analysis of 1,652 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.
Mean age of participants was 62 years and 60% were female. Mean 25(OH)D was higher in whites than blacks (25.5 ng/ml versus 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 (p>0.05). Over a median of 16.6 years, there were 145 incident hospitalized dementia cases. Though not statistically significant, lower levels of 25(OH)D were suggestive of an association with increased dementia risk (HR lowest versus highest race-specific tertile: whites 1.32 [95% CI: 0.69, 2.55]; blacks 1.53 [95% CI: 0.84, 2.79]).
In contrast to prior studies performed in older white populations, our study did not find significant associations between lower levels of 25(OH)D measured in late-middle age black or white participants with lower cognitive test scores at baseline, change in scores over time, or dementia risk.
PMCID: PMC4114998  PMID: 24846449
Vitamin D; Cognition; Dementia; ARIC Study
2.  Comparison of Racial Differences in Plaque Composition and Stenosis among HIV Positive and Negative Men from the Multicenter Aids Cohort Study (MACS) 
The American journal of cardiology  2014;114(3):369-375.
Previous studies demonstrated that blacks have less coronary artery calcification (CAC) than whites. We evaluated racial differences in plaque composition and stenosis in the Multicenter AIDS Cohort Study (MACS). HIV positive and negative men completed non-contrast cardiac CT if they were 40–70 years, weighed <300 pounds, and had no prior history of cardiac surgery or revascularization, and if eligible, coronary CT angiography (CTA). There were 1001 men who underwent CT scans and 759 men had CTA. We measured CAC on non-contrast CT, and total plaque, non-calcified, calcified, and mixed plaque, and identified coronary stenosis >50% on CTA. The association of presence and extent of plaque with race was determined after adjustment for HIV serostatus, cardiovascular risk factors and measures of socioeconomic status. The prevalences of any plaque on CTA and non-calcified plaque were not different between black and white men; however, black men had lower prevalences of CAC (Prevalence ratio (PR)=0.79, p=0.01), calcified plaque (PR=0.69, p=0.002), and stenosis >50% (PR=0.59, p=0.009). There were no associations between black race and extent of plaque in fully adjusted models. Using log-linear regression, black race was associated with a lower extent of any plaque on CTA in HIV positive men (estimate=−0.24, p=0.051) but not in HIV negative men (0.12, p=0.50, HIV interaction p=0.005). In conclusion, a lower prevalence of CAC in black compared to white men appears to reflect less calcification of plaque and stenosis rather than a lower overall prevalence of plaque.
PMCID: PMC4143765  PMID: 24929623
Epidemiology; plaque; coronary angiography; coronary artery disease; HIV
3.  Epicardial Fat is Associated with Duration of Antiretroviral Therapy and Coronary Atherosclerosis: The Multicenter AIDS Cohort Study 
AIDS (London, England)  2014;28(11):1635-1644.
Cytokines released by epicardial fat are implicated in the pathogenesis of atherosclerosis. HIV infection and anti-retroviral therapy have been associated with changes in body fat distribution and coronary artery disease. We sought to determine if HIV infection is associated with greater epicardial fat and if epicardial fat is associated with subclinical coronary atherosclerosis.
We studied 579 HIV-infected and 353 HIV-uninfected men age 40 to 70 years with non-contrast computed tomography (CT) to measure epicardial adipose tissue volume (EAT) and coronary artery calcium (CAC). Total plaque score (TPS), and plaque subtypes (non-calcified, calcified and mixed) were measured by coronary CT angiography in 706 men.
We evaluated the association between EAT and HIV serostatus, and the association of EAT with subclinical atherosclerosis, adjusting for age, race and serostatus and with additional cardiovascular (CV) risk factors and tested for modifying effects of HIV serostatus.
HIV-infected men had greater EAT than HIV-uninfected men (p=0.001). EAT was positively associated with duration of antiretroviral therapy (p=0.02), specifically AZT (p<0.05). EAT was associated with presence of any coronary artery plaque (p=0.006) and non-calcified plaque (p=0.001), adjusting for age, race, serostatus and CV risk factors. Among men with CAC, EAT was associated with CAC extent (p=0.006). HIV serostatus did not modify associations between EAT and either CAC extent or presence of plaque.
Greater epicardial fat volume in HIV-infected men and its association with coronary plaque and antiretroviral therapy duration suggest potential mechanisms that might lead to increased risk for cardiovascular disease in HIV.
PMCID: PMC4169787  PMID: 24809732
Imaging; plaque; risk factors; HIV; ART
4.  Association of the Lipoprotein Receptor SCARB1 Common Missense Variant rs4238001 with Incident Coronary Heart Disease 
PLoS ONE  2015;10(5):e0125497.
Previous studies in mice and humans have implicated the lipoprotein receptor SCARB1 in association with atherosclerosis and lipid levels. In the current study, we sought to examine association of SCARB1 missense single nucleotide polymorphism (SNP) rs4238001 with incident coronary heart disease (CHD).
Methods and Results
Genotypes for rs4238001 were imputed for 2,319 White, 1,570 African American, and 1,292 Hispanic-American MESA participants using the 1,000 Genomes reference set. Cox proportional hazards models were used to determine association of rs4238001 with incident CHD, with adjustments for age, sex, study site, principal components of ancestry, body mass index, diabetes status, serum creatinine, lipid levels, hypertension status, education and smoking exposure. Meta-analysis across race/ethnic groups within MESA showed statistically significant association of the T allele with higher risk of CHD under a consistent and formally adjudicated definition of CHD events in this contemporary cohort study (hazard ratio [HR]=1.49, 95% CI [1.04, 2.14], P = 0.028). Analyses combining MESA with additional population-based cohorts expanded our samples in Whites (total n = 11,957 with 871 CHD events) and African Americans (total n = 5,962 with 355 CHD events) and confirmed an increased risk of CHD overall (HR of 1.19 with 95% CI [1.04, 1.37], P = 0.013), in African Americans (HR of 1.49 with 95% CI [1.07, 2.06], P = 0.019), in males (HR of 1.29 with 95% CI [1.08, 1.54], P = 4.91x10-3) and in White males (HR of 1.24 with 95% CI [1.03, 1.51], P = 0.026).
SCARB1 missense rs4238001 is statistically significantly associated with incident CHD across a large population of multiple race/ethnic groups.
PMCID: PMC4439156  PMID: 25993026
5.  Age-related variations in the methylome associated with gene expression in human monocytes and T cells 
Nature communications  2014;5:5366.
Age-related variations in DNA methylation have been reported; however, the functional relevance of these differentially methylated sites (age-dMS) are unclear. Here we report potentially functional age-dMS, defined as age- and cis-gene expression-associated methylation sites (age-eMS), identified by integrating genome-wide CpG methylation and gene expression profiles collected ex vivo from circulating T cells (227 CD4+ samples) and monocytes (1,264 CD14+ samples, age range: 55–94 years). None of the age-eMS detected in 227 T cell samples are detectable in 1,264 monocyte samples, in contrast to the majority of age-dMS detected in T cells that replicated in monocytes. Age-eMS tend to be hypomethylated with older age, located in predicted enhancers, and preferentially linked to expression of antigen processing and presentation genes. These results identify and characterize potentially functional age-related methylation in human T cells and monocytes, and provide novel insights into the role age-dMS may play in the aging process.
PMCID: PMC4280798  PMID: 25404168
6.  Association of Low-Density Lipoprotein Cholesterol–Related Genetic Variants With Aortic Valve Calcium and Incident Aortic Stenosis 
JAMA  2014;312(17):1764-1771.
Plasma low-density lipoprotein cholesterol (LDL-C) has been associated with aortic stenosis in observational studies; however, randomized trials with cholesterol-lowering therapies in individuals with established valve disease have failed to demonstrate reduced disease progression.
To evaluate whether genetic data are consistent with an association between LDL-C, high-density lipoprotein cholesterol (HDL-C), or triglycerides (TG) and aortic valve disease.
Using a Mendelian randomization study design, we evaluated whether weighted genetic risk scores (GRSs), a measure of the genetic predisposition to elevations in plasma lipids, constructed using single-nucleotide polymorphisms identified in genome-wide association studies for plasma lipids, were associated with aortic valve disease. We included community-based cohorts participating in the CHARGE consortium (n = 6942), including the Framingham Heart Study (cohort inception to last follow-up: 1971-2013; n = 1295), Multi-Ethnic Study of Atherosclerosis (2000-2012; n = 2527), Age Gene/Environment Study-Reykjavik (2000-2012; n = 3120), and the Malmö Diet and Cancer Study (MDCS, 1991-2010; n = 28 461).
Aortic valve calcium quantified by computed tomography in CHARGE and incident aortic stenosis in the MDCS.
The prevalence of aortic valve calcium across the 3 CHARGE cohorts was 32% (n = 2245). In the MDCS, over a median follow-up time of 16.1 years, aortic stenosis developed in 17 per 1000 participants (n = 473) and aortic valve replacement for aortic stenosis occurred in 7 per 1000 (n = 205). Plasma LDL-C, but not HDL-C or TG, was significantly associated with incident aortic stenosis (hazard ratio [HR] per mmol/L, 1.28; 95% CI, 1.04-1.57; P = .02; aortic stenosis incidence: 1.3% and 2.4% in lowest and highest LDL-C quartiles, respectively). The LDL-C GRS, but not HDL-C or TG GRS, was significantly associated with presence of aortic valve calcium in CHARGE (odds ratio [OR] per GRS increment, 1.38; 95% CI, 1.09-1.74; P = .007) and with incident aortic stenosis in MDCS (HR per GRS increment, 2.78; 95% CI, 1.22-6.37; P = .02; aortic stenosis incidence: 1.9% and 2.6% in lowest and highest GRS quartiles, respectively). In sensitivity analyses excluding variants weakly associated with HDL-C or TG, the LDL-C GRS remained associated with aortic valve calcium (P = .03) and aortic stenosis (P = .009). In instrumental variable analysis, LDL-C was associated with an increase in the risk of incident aortic stenosis (HR per mmol/L, 1.51; 95% CI, 1.07-2.14; P = .02).
Genetic predisposition to elevated LDL-C was associated with presence of aortic valve calcium and incidence of aortic stenosis, providing evidence supportive of a causal association between LDL-C and aortic valve disease. Whether earlier intervention to reduce LDL-C could prevent aortic valve disease merits further investigation.
PMCID: PMC4280258  PMID: 25344734
7.  Incident stroke is associated with common carotid artery diameter and not common carotid artery intima-media thickness 
Background and Purpose
The common carotid artery (CCA) inter-adventitial diameter (IAD) is measured on ultrasound images as the distance between the media-adventitia interfaces of the near and far walls. It is associated with common carotid intima-media thickness (IMT) and left ventricular mass and might therefore also have an association with incident stroke.
We studied 6255 individuals free of coronary heart disease and stroke at baseline with mean age of 62.2 years (47.3% men), members of a multi-ethnic community based cohort of whites, blacks, Hispanics, and Chinese. Ischemic stroke events were centrally adjudicated. CCA IAD and IMT were measured. Cases with incident atrial fibrillation (n = 385) were excluded. Multivariable Cox proportional hazards models were generated with time to ischemic event as outcome, adjusting for risk factors.
There were 115 first time ischemic strokes at 7.8 years of follow-up. CCA IAD was a significant predictor of ischemic stroke (Hazard ratio: 1.86; 95%CI 1.59, 2.17 per mm) and remained so after adjustment for risk factors and common carotid IMT with a hazard ratio of 1.52 per mm (95% CI: 1.22, 1.88). Common carotid IMT was not an independent predictor after adjustment (hazard ratio 0.14; 95% CI: 0.14, 1.19).
While common carotid IMT is not associated with stroke, inter-adventitial diameter of the common carotid artery is independently associated with first time incident ischemic stroke even after adjusting for IMT. Our hypothesis that this is in part due to the effects of exposure to blood pressure needs confirmation by other studies.
PMCID: PMC4270293  PMID: 24643408
8.  Transcriptomic profiles of aging in purified human immune cells 
BMC Genomics  2015;16(1):333.
Transcriptomic studies hold great potential towards understanding the human aging process. Previous transcriptomic studies have identified many genes with age-associated expression levels; however, small samples sizes and mixed cell types often make these results difficult to interpret.
Using transcriptomic profiles in CD14+ monocytes from 1,264 participants of the Multi-Ethnic Study of Atherosclerosis (aged 55–94 years), we identified 2,704 genes differentially expressed with chronological age (false discovery rate, FDR ≤ 0.001). We further identified six networks of co-expressed genes that included prominent genes from three pathways: protein synthesis (particularly mitochondrial ribosomal genes), oxidative phosphorylation, and autophagy, with expression patterns suggesting these pathways decline with age. Expression of several chromatin remodeler and transcriptional modifier genes strongly correlated with expression of oxidative phosphorylation and ribosomal protein synthesis genes. 17% of genes with age-associated expression harbored CpG sites whose degree of methylation significantly mediated the relationship between age and gene expression (p < 0.05). Lastly, 15 genes with age-associated expression were also associated (FDR ≤ 0.01) with pulse pressure independent of chronological age.
Comparing transcriptomic profiles of CD14+ monocytes to CD4+ T cells from a subset (n = 423) of the population, we identified 30 age-associated (FDR < 0.01) genes in common, while larger sets of differentially expressed genes were unique to either T cells (188 genes) or monocytes (383 genes). At the pathway level, a decline in ribosomal protein synthesis machinery gene expression with age was detectable in both cell types.
An overall decline in expression of ribosomal protein synthesis genes with age was detected in CD14+ monocytes and CD4+ T cells, demonstrating that some patterns of aging are likely shared between different cell types. Our findings also support cell-specific effects of age on gene expression, illustrating the importance of using purified cell samples for future transcriptomic studies. Longitudinal work is required to establish the relationship between identified age-associated genes/pathways and aging-related diseases.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1522-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4417516  PMID: 25898983
Aging; Monocyte; T cell; Transcriptome; Mitochondrial ribosome; Translation; Protein synthesis; Ribonucleoprotein complex; Oxidative phosphorylation; Autophagy; Methylation
9.  Determinants of intrathoracic adipose tissue volume and associations with cardiovascular disease risk factors in Amish 
Hypothesizing that intrathoracic fat might exert local effects on the coronary vasculature, we assessed the association of intrathoracic fat volume and its two subcomponents with coronary artery calcification (CAC) in 909 relatively healthy Amish adults.
Design and Methods
Intrathoracic fat, which is comprised of fat between the surface of the heart and the visceral epicardium (epicardial fat) and fat around the heart but outside of the fibrous pericardium (pericardial fat), was measured from electron beam CT scans. We examined the association between intrathoracic fat volume and cardiovascular disease risk factors in multivariate regression model.
Fat volume in the epicardial and pericardial compartments were highly correlated with each other and with body mass index. Neither CAC extent nor CAC presence (Agatston score>0) was associated with increased intrathoracic fat volume in sex-stratified models adjusting for age (p>0.10). Intrathoracic fat volume was significantly correlated with higher systolic/diastolic blood pressure, pulse pressure, fasting glucose, insulin, triglyceride and lower high-density lipoprotein cholesterol in sex-stratified models adjusting for age (p<0.05). However, associations were attenuated after further adjustment for body mass index.
These data do not provide support for a significant role for intrathoracic fat in the development of CAC.
PMCID: PMC4109402  PMID: 24477004
Ectopic fat; Intrathoracic fat; Epicardial fat; Obesity; Coronary artery calcification; Cardiovascular diseases
10.  Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization 
Arking, Dan E. | Pulit, Sara L. | Crotti, Lia | van der Harst, Pim | Munroe, Patricia B. | Koopmann, Tamara T. | Sotoodehnia, Nona | Rossin, Elizabeth J. | Morley, Michael | Wang, Xinchen | Johnson, Andrew D. | Lundby, Alicia | Gudbjartsson, Daníel F. | Noseworthy, Peter A. | Eijgelsheim, Mark | Bradford, Yuki | Tarasov, Kirill V. | Dörr, Marcus | Müller-Nurasyid, Martina | Lahtinen, Annukka M. | Nolte, Ilja M. | Smith, Albert Vernon | Bis, Joshua C. | Isaacs, Aaron | Newhouse, Stephen J. | Evans, Daniel S. | Post, Wendy S. | Waggott, Daryl | Lyytikäinen, Leo-Pekka | Hicks, Andrew A. | Eisele, Lewin | Ellinghaus, David | Hayward, Caroline | Navarro, Pau | Ulivi, Sheila | Tanaka, Toshiko | Tester, David J. | Chatel, Stéphanie | Gustafsson, Stefan | Kumari, Meena | Morris, Richard W. | Naluai, Åsa T. | Padmanabhan, Sandosh | Kluttig, Alexander | Strohmer, Bernhard | Panayiotou, Andrie G. | Torres, Maria | Knoflach, Michael | Hubacek, Jaroslav A. | Slowikowski, Kamil | Raychaudhuri, Soumya | Kumar, Runjun D. | Harris, Tamara B. | Launer, Lenore J. | Shuldiner, Alan R. | Alonso, Alvaro | Bader, Joel S. | Ehret, Georg | Huang, Hailiang | Kao, W.H. Linda | Strait, James B. | Macfarlane, Peter W. | Brown, Morris | Caulfield, Mark J. | Samani, Nilesh J. | Kronenberg, Florian | Willeit, Johann | Smith, J. Gustav | Greiser, Karin H. | zu Schwabedissen, Henriette Meyer | Werdan, Karl | Carella, Massimo | Zelante, Leopoldo | Heckbert, Susan R. | Psaty, Bruce M. | Rotter, Jerome I. | Kolcic, Ivana | Polašek, Ozren | Wright, Alan F. | Griffin, Maura | Daly, Mark J. | Arnar, David O. | Hólm, Hilma | Thorsteinsdottir, Unnur | Denny, Joshua C. | Roden, Dan M. | Zuvich, Rebecca L. | Emilsson, Valur | Plump, Andrew S. | Larson, Martin G. | O'Donnell, Christopher J. | Yin, Xiaoyan | Bobbo, Marco | D'Adamo, Adamo P. | Iorio, Annamaria | Sinagra, Gianfranco | Carracedo, Angel | Cummings, Steven R. | Nalls, Michael A. | Jula, Antti | Kontula, Kimmo K. | Marjamaa, Annukka | Oikarinen, Lasse | Perola, Markus | Porthan, Kimmo | Erbel, Raimund | Hoffmann, Per | Jöckel, Karl-Heinz | Kälsch, Hagen | Nöthen, Markus M. | consortium, HRGEN | den Hoed, Marcel | Loos, Ruth J.F. | Thelle, Dag S. | Gieger, Christian | Meitinger, Thomas | Perz, Siegfried | Peters, Annette | Prucha, Hanna | Sinner, Moritz F. | Waldenberger, Melanie | de Boer, Rudolf A. | Franke, Lude | van der Vleuten, Pieter A. | Beckmann, Britt Maria | Martens, Eimo | Bardai, Abdennasser | Hofman, Nynke | Wilde, Arthur A.M. | Behr, Elijah R. | Dalageorgou, Chrysoula | Giudicessi, John R. | Medeiros-Domingo, Argelia | Barc, Julien | Kyndt, Florence | Probst, Vincent | Ghidoni, Alice | Insolia, Roberto | Hamilton, Robert M. | Scherer, Stephen W. | Brandimarto, Jeffrey | Margulies, Kenneth | Moravec, Christine E. | Fabiola Del, Greco M. | Fuchsberger, Christian | O'Connell, Jeffrey R. | Lee, Wai K. | Watt, Graham C.M. | Campbell, Harry | Wild, Sarah H. | El Mokhtari, Nour E. | Frey, Norbert | Asselbergs, Folkert W. | Leach, Irene Mateo | Navis, Gerjan | van den Berg, Maarten P. | van Veldhuisen, Dirk J. | Kellis, Manolis | Krijthe, Bouwe P. | Franco, Oscar H. | Hofman, Albert | Kors, Jan A. | Uitterlinden, André G. | Witteman, Jacqueline C.M. | Kedenko, Lyudmyla | Lamina, Claudia | Oostra, Ben A. | Abecasis, Gonçalo R. | Lakatta, Edward G. | Mulas, Antonella | Orrú, Marco | Schlessinger, David | Uda, Manuela | Markus, Marcello R.P. | Völker, Uwe | Snieder, Harold | Spector, Timothy D. | Ärnlöv, Johan | Lind, Lars | Sundström, Johan | Syvänen, Ann-Christine | Kivimaki, Mika | Kähönen, Mika | Mononen, Nina | Raitakari, Olli T. | Viikari, Jorma S. | Adamkova, Vera | Kiechl, Stefan | Brion, Maria | Nicolaides, Andrew N. | Paulweber, Bernhard | Haerting, Johannes | Dominiczak, Anna F. | Nyberg, Fredrik | Whincup, Peter H. | Hingorani, Aroon | Schott, Jean-Jacques | Bezzina, Connie R. | Ingelsson, Erik | Ferrucci, Luigi | Gasparini, Paolo | Wilson, James F. | Rudan, Igor | Franke, Andre | Mühleisen, Thomas W. | Pramstaller, Peter P. | Lehtimäki, Terho J. | Paterson, Andrew D. | Parsa, Afshin | Liu, Yongmei | van Duijn, Cornelia | Siscovick, David S. | Gudnason, Vilmundur | Jamshidi, Yalda | Salomaa, Veikko | Felix, Stephan B. | Sanna, Serena | Ritchie, Marylyn D. | Stricker, Bruno H. | Stefansson, Kari | Boyer, Laurie A. | Cappola, Thomas P. | Olsen, Jesper V. | Lage, Kasper | Schwartz, Peter J. | Kääb, Stefan | Chakravarti, Aravinda | Ackerman, Michael J. | Pfeufer, Arne | de Bakker, Paul I.W. | Newton-Cheh, Christopher
Nature genetics  2014;46(8):826-836.
The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal Mendelian Long QT Syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals we identified 35 common variant QT interval loci, that collectively explain ∼8-10% of QT variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 novel QT loci in 298 unrelated LQTS probands identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode for proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies novel candidate genes for ventricular arrhythmias, LQTS,and SCD.
PMCID: PMC4124521  PMID: 24952745
genome-wide association study; QT interval; Long QT Syndrome; sudden cardiac death; myocardial repolarization; arrhythmias
11.  Beat‐to‐Beat Spatiotemporal Variability in the T Vector Is Associated With Sudden Cardiac Death in Participants Without Left Ventricular Hypertrophy: The Atherosclerosis Risk in Communities (ARIC) Study 
Despite advances in prevention and treatment of cardiovascular disease, sudden cardiac death (SCD) remains a clinical challenge. Risk stratification in the general population is needed.
Methods and Results
Beat‐to‐beat spatiotemporal variability in the T vector was measured as the mean angle between consecutive T‐wave vectors (mean TT′ angle) on standard 12‐lead ECGs in 14 024 participants in the Atherosclerosis Risk in Communities (ARIC) study. Subjects with left ventricular hypertrophy, atrial arrhythmias, frequent ectopy, ventricular pacing, or QRS duration ≥120 ms were excluded. The mean spatial TT′ angle was 5.21±3.55°. During a median of 14 years of follow‐up, 235 SCDs occurred (1.24 per 1000 person‐years). After adjustment for demographics, coronary heart disease risk factors, and known ECG markers for SCD, mean TT′ angle was independently associated with SCD (hazard ratio 1.089; 95% CI 1.044 to 1.137; P<0.0001). A mean TT′ angle >90th percentile (>9.57°) was associated with a 2‐fold increase in the hazard for SCD (hazard ratio 2.01; 95% CI 1.28 to 3.16; P=0.002). In a subgroup of patients with T‐vector amplitude ≥0.2 mV, the association with SCD was almost twice as strong (hazard ratio 3.92; 95% CI 1.91 to 8.05; P<0.0001). A significant interaction between mean TT′ angle and age was found: TT′ angle was associated with SCD in participants aged <55 years (hazard ratio 1.096; 95% CI 0.043 to 1.152; P<0.0001) but not in participants aged ≥55 years (Pinteraction=0.009).
In a large, prospective, community‐based cohort of left ventricular hypertrophy–free participants, increased beat‐to‐beat spatiotemporal variability in the T vector, as assessed by increasing TT′ angle, was associated with SCD.
PMCID: PMC4330061  PMID: 25600143
atherosclerosis; electrocardiography; electrophysiology; epidemiology; sudden cardiac death; TT′ angle
12.  Methylomics of gene expression in human monocytes 
Human Molecular Genetics  2013;22(24):5065-5074.
DNA methylation is one of several epigenetic mechanisms that contribute to the regulation of gene expression; however, the extent to which methylation of CpG dinucleotides correlates with gene expression at the genome-wide level is still largely unknown. Using purified primary monocytes from subjects in a large community-based cohort (n = 1264), we characterized methylation (>485 000 CpG sites) and mRNA expression (>48K transcripts) and carried out genome-wide association analyses of 8370 expression phenotypes. We identified 11 203 potential cis-acting CpG loci whose degree of methylation was associated with gene expression (eMS) at a false discovery rate threshold of 0.001. Most of the associations were consistent in effect size and direction of effect across sex and three ethnicities. Contrary to expectation, these eMS were not predominately enriched in promoter regions, or CpG islands, but rather in the 3′ UTR, gene bodies, CpG shores or ‘offshore’ sites, and both positive and negative correlations between methylation and expression were observed across all locations. eMS were enriched for regions predicted to be regulatory by ENCODE (Encyclopedia of DNA Elements) data in multiple cell types, particularly enhancers. One of the strongest association signals detected (P < 2.2 × 10−308) was a methylation probe (cg17005068) in the promoter/enhancer region of the glutathione S-transferase theta 1 gene (GSTT1, encoding the detoxification enzyme) with GSTT1 mRNA expression. Our study provides a detailed description of the epigenetic architecture in human monocytes and its relationship to gene expression. These data may help prioritize interrogation of biologically relevant methylation loci and provide new insights into the epigenetic basis of human health and diseases.
PMCID: PMC3836482  PMID: 23900078
13.  Electrocardiographic Deep Terminal Negativity of the P Wave in V1 and Risk of Sudden Cardiac Death: The Atherosclerosis Risk in Communities (ARIC) Study 
Identifying individuals at risk for sudden cardiac death (SCD) is of critical importance. Electrocardiographic (ECG) deep terminal negativity of P wave in V1 (DTNPV1), a marker of left atrial abnormality, has been associated with increased risk of all‐cause and cardiovascular mortality. We hypothesized that DTNPV1 is associated with increased risk of sudden cardiac death (SCD).
Methods and Results
This analysis included 15 375 participants (54.1±5.8 years, 45% men, 73% whites) from the Atherosclerosis Risk in Communities (ARIC) study. DTNPV1 was defined from the resting 12‐lead ECG as presence of biphasic P wave (positive/negative) in V1 with the amplitude of the terminal negative phase >100 μV, or one small box on ECG scale. After a median of 14 years of follow‐up, 311 cases of SCD occurred. In unadjusted Cox regression, DTNPV1 was associated with an 8‐fold increased risk of SCD (HR 8.21; [95%CI 5.27 to 12.79]). Stratified by race and study center, and adjusted for age, sex, coronary heart disease (CHD), and ECG risk factors, as well as atrial fibrillation (AF), stroke, CHD, and heart failure (HF) as time‐updated variables, the risk of SCD associated with DTNPV1 remained significant (2.49, [1.51–4.10]). DTNPV1 improved reclassification: additional 3.4% of individuals were appropriately reclassified into a higher SCD risk group, as compared with traditional CHD risk factors alone. In fully adjusted models DTNPV1 was associated with increased risk of non‐fatal events: AF (5.02[3.23–7.80]), CHD (2.24[1.43–3.53]), HF (1.90[1.19–3.04]), and trended towards increased risk of stroke (1.88[0.99–3.57]).
DTNPV1 is predictive of SCD suggesting its potential utility in risk stratification in the general population.
PMCID: PMC4338733  PMID: 25416036
electrocardiogram; risk stratification; sudden cardiac death
14.  Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins 
Postmus, Iris | Trompet, Stella | Deshmukh, Harshal A. | Barnes, Michael R. | Li, Xiaohui | Warren, Helen R. | Chasman, Daniel I. | Zhou, Kaixin | Arsenault, Benoit J. | Donnelly, Louise A. | Wiggins, Kerri L. | Avery, Christy L. | Griffin, Paula | Feng, QiPing | Taylor, Kent D. | Li, Guo | Evans, Daniel S. | Smith, Albert V. | de Keyser, Catherine E. | Johnson, Andrew D. | de Craen, Anton J. M. | Stott, David J. | Buckley, Brendan M. | Ford, Ian | Westendorp, Rudi G. J. | Eline Slagboom, P. | Sattar, Naveed | Munroe, Patricia B. | Sever, Peter | Poulter, Neil | Stanton, Alice | Shields, Denis C. | O’Brien, Eoin | Shaw-Hawkins, Sue | Ida Chen, Y.-D. | Nickerson, Deborah A. | Smith, Joshua D. | Pierre Dubé, Marie | Matthijs Boekholdt, S. | Kees Hovingh, G. | Kastelein, John J. P. | McKeigue, Paul M. | Betteridge, John | Neil, Andrew | Durrington, Paul N. | Doney, Alex | Carr, Fiona | Morris, Andrew | McCarthy, Mark I. | Groop, Leif | Ahlqvist, Emma | Bis, Joshua C. | Rice, Kenneth | Smith, Nicholas L. | Lumley, Thomas | Whitsel, Eric A. | Stürmer, Til | Boerwinkle, Eric | Ngwa, Julius S. | O’Donnell, Christopher J. | Vasan, Ramachandran S. | Wei, Wei-Qi | Wilke, Russell A. | Liu, Ching-Ti | Sun, Fangui | Guo, Xiuqing | Heckbert, Susan R | Post, Wendy | Sotoodehnia, Nona | Arnold, Alice M. | Stafford, Jeanette M. | Ding, Jingzhong | Herrington, David M. | Kritchevsky, Stephen B. | Eiriksdottir, Gudny | Launer, Leonore J. | Harris, Tamara B. | Chu, Audrey Y. | Giulianini, Franco | MacFadyen, Jean G. | Barratt, Bryan J. | Nyberg, Fredrik | Stricker, Bruno H. | Uitterlinden, André G. | Hofman, Albert | Rivadeneira, Fernando | Emilsson, Valur | Franco, Oscar H. | Ridker, Paul M. | Gudnason, Vilmundur | Liu, Yongmei | Denny, Joshua C. | Ballantyne, Christie M. | Rotter, Jerome I. | Adrienne Cupples, L. | Psaty, Bruce M. | Palmer, Colin N. A. | Tardif, Jean-Claude | Colhoun, Helen M. | Hitman, Graham | Krauss, Ronald M. | Wouter Jukema, J | Caulfield, Mark J.
Nature Communications  2014;5:5068.
Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.
Statins are effectively used to prevent and manage cardiovascular disease, but patient response to these drugs is highly variable. Here, the authors identify two new genes associated with the response of LDL cholesterol to statins and advance our understanding of the genetic basis of drug response.
PMCID: PMC4220464  PMID: 25350695
15.  Vitamin D and Subclinical Cerebrovascular Disease 
JAMA neurology  2014;71(7):863-871.
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.
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.
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).
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.
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.
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.
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.
PMCID: PMC4218739  PMID: 24861877
16.  Risk Factors for Fatty Liver in the Multicenter AIDS Cohort Study 
Human immunodeficiency virus (HIV) infection and antiretroviral therapy (ART) may increase the risk of fatty liver disease. We determined the prevalence of and risk factors for fatty liver by comparing HIV-infected men with HIV-uninfected men who have sex with men in the Multicenter AIDS Cohort Study (MACS).
In 719 MACS participants who consumed less than three alcoholic drinks daily, fatty liver was defined as a liver-to-spleen attenuation ratio < 1 on noncontrast computed tomography (CT). We genotyped single nucleotide polymorphisms in the patatin-like phospholipase domain-containing 3 (PNPLA3) gene and in other genes previously associated with nonalcoholic fatty liver disease. Risk factors for fatty liver were determined using multivariable logistic regression.
Among 254 HIV-uninfected men and 465 HIV-infected men, 56 % were White with median age 53 years and median body mass index 25.8 kg/m 2. The vast majority of HIV-infected men (92 %) were on ART, and 87 % of the HIV-infected men were treated with a nucleoside reverse transcriptase inhibitor for a median duration of 8.5 years. Overall, 15 % of the cohort had fatty liver, which was more common in the HIV-uninfected compared with the HIV-infected men (19 vs. 13 %, P= 0.02). In multivariable analysis, HIV infection was associated with a lower prevalence of fatty liver (odds ratio (OR) = 0.44, P= 0.002), whereas a higher prevalence of fatty liver was seen in participants with PNPLA3 (rs738409) non-CC genotype (OR = 2.06, P= 0.005), more abdominal visceral adipose tissue (OR = 1.08 per 10 cm2, P< 0.001), and homeostatic model assessment of insulin resistance (HOMA-IR) ≥ 4.9 (OR = 2.50, P= 0.001). Among HIV-infected men, PNPLA3 (rs738409) non-CC genotype was associated with a higher prevalence of fatty liver (OR = 3.30, P= 0.001) and cumulative dideoxynucleoside exposure (OR = 1.44 per 5 years, P= 0.02).
CT-defined fatty liver is common among men at risk for HIV infection and is associated with greater visceral adiposity, HOMA-IR, and PNPLA3 (rs738409). Although treated HIV infection was associated with a lower prevalence of fatty liver, prolonged exposure to dideoxynucleo side analogs is associated with higher prevalence.
PMCID: PMC4133993  PMID: 24642579
17.  Associations between HIV Infection and Subclinical Coronary Atherosclerosis: The Multicenter AIDS Cohort Study (MACS) 
Annals of internal medicine  2014;160(7):458-467.
Coronary artery disease (CAD) has been associated with HIV infection; however data are not consistent.
We performed cardiac CT to determine whether HIV-infected men have more coronary atherosclerosis than uninfected men.
Cross-sectional study within the Multicenter AIDS Cohort Study(MACS).
HIV-infected (n=618) and –uninfected (n=383) men who have sex with men (MSM) had non-contrast and contrast enhanced cardiac CT if they were between 40–70 years, weighed <300 pounds, and had no history of coronary revascularization.
Presence and extent, for those with plaque, of coronary artery calcium (CAC) on non-contrast CT, and of any plaque, non-calcified, mixed or calcified plaque and stenosis on CT angiography.
1001 men underwent non-contrast CT of whom 759 had coronary CT angiography. After adjusting for age, race, center, and cohort, HIV-infected men had a greater prevalence of CAC [Prevalence ratio(PR)=1.21, 95% confidence interval (CI) 1.08–1.35, p=0.001], and any plaque [PR=1.14(1.05–1.24),p=0.001], including non-calcified plaque [PR=1.28(1.13–1.45),p<0.001) and mixed plaque [PR=1.35(1.10–1.65),p=0.004] than HIV-uninfected men. Associations between HIV-infection and any plaque and non-calcified plaque remained significant (p<0.005) after CAD risk factor adjustment. HIV-infected men also had a greater extent of non-calcified plaque after CAD risk factor adjustment (p=0.026). HIV-infected men had a greater prevalence of coronary artery stenosis>50% than HIV-uninfected men [PR=1.48(1.06–2.07),p=0.020), but not after CAD risk factor adjustment. Longer duration of highly active antiretroviral therapy [PR=1.09(1.02–1.17), p=0.007,per year] and lower nadir CD4+ T-cell count [PR=0.80(0.69–0.94),p=0.005, per 100 cells] were associated with coronary stenosis>50%.
Coronary artery plaque, especially non-calcified plaque, is more prevalent and extensive in HIV-infected men, independent of CAD risk factors.
Cross-sectional observational study design and inclusion of only men.
Primary Funding Source
PMCID: PMC4143766  PMID: 24687069
18.  Computed Tomography-Derived Cardiovascular Risk Markers, Incident Cardiovascular Events, and All-Cause Mortality in Non- Diabetics. The Multi-Ethnic Study of Atherosclerosis 
We assess the improvement in discrimination afforded by the addition thoracic aorta calcium (TAC), aortic valve calcification (AVC), mitral annular calcification (MAC), pericardial adipose tissue volume (PAT) and liver attenuation (LA) to Framingham risk score(FRS) + coronary artery calcium (CAC) for incident CHD/CVD in a multi ethnic cohort.
Methods and Results
A total 5745(2710 were intermediate Framingham risk, 210 CVD and 155 CHD events) 251 had adjudicated CHD, 346 had CVD events, 321 died after 9 years of follow-up. Cox proportional hazard, receiver operator curve (ROC) and net reclassification improvement (NRI) analyses.
In the whole cohort and also when the analysis was restricted to only the intermediate risk participants: CAC, TAC, AVC and MAC were all significantly associated with incident CVD/CHD/ mortality; CAC had the strongest association. When added to the FRS, CAC had the highest area under the curve (AUC) for the prediction of incident CHD/CVD; LA had the least. The addition of TAC, AVC, MAC, PAT and LA to FRS + CAC all resulted in a significant reduction in AUC for incident CHD [0.712 vs. 0.646, 0.655, 0.652, 0.648 and 0.569; all p<0.01 respectively] in participants with intermediate FRS. The addition of CAC to FRS resulted in an NRI of 0.547 for incident CHD in the intermediate risk group. The NRI when TAC, AVC, MAC, PAT and LA were added to FRS + CAC were 0.024, 0.026, 0.019, 0.012 and 0.012 respectively, for incident CHD in the intermediate risk group. Similar results were obtained for incident CVD in the intermediate risk group and also when the whole cohort was used instead of the intermediate FRS group.
The addition of CAC to the FRS provides superior discrimination especially in intermediate risk individuals compared with the addition of TAC, AVC, MAC, PAT or LA for incident CHD/CVD. Compared with FRS + CAC, the addition of TAC, AVC, MAC, PAT or LA individually to FRS + CAC worsens the discrimination for incident CHD/CVD. These CT risk markers are unlikely to be useful for improving cardiovascular risk prediction.
PMCID: PMC4150859  PMID: 23689526
cardiac CT derived risk factors; coronary heart disease; cardiovascular events; risk prediction
19.  No Association of 9p21 with Arterial Elasticity and Retinal Microvascular Findings 
Atherosclerosis  2013;230(2):301-303.
How 9p21 variation affects risk of cardiovascular disease is unclear, so we assessed whether 9p21 variants are associated with arterial elasticity or retinal microvascular findings.
In the prospective Multi-Ethnic Study of Atherosclerosis (MESA) we assessed 378 SNPs in the 9p21 locus. Within four ethnic groups, we used an additive genetic model to relate the 9p21 SNPs to five vascular phenotypes: small and large elasticity derived from radial diastolic pulse contour analysis; Young’s elastic modulus from carotid artery ultrasound measurements; and the diameter of the central retinal arteries and veins.
In neither ethnic-specific nor pooled data was there any statistically significant association between any of the 9p21 SNPs and any of the five vascular phenotypes.
Our study does not support an association of 9p21 variation with arterial elasticity or retinal microvascular abnormalities.
PMCID: PMC3787319  PMID: 24075760
Prospective study; 9p21 SNP; retinal microvascular abnormalities; arterial elasticity
20.  Progression of Coronary Calcium and Incident Coronary Heart Disease Events: The Multi-Ethnic Study of Atherosclerosis 
Coronary artery calcium (CAC) predicts coronary heart disease (CHD) events and serial measurement of CAC has been proposed to evaluate atherosclerosis progression. We examined whether progression of CAC is a predictor of future CHD events.
Methods and Results
We studied 6,778 persons (52.8% female) aged 45–84 years from the Multi-Ethnic Study of Atherosclerosis. 5,682 persons had baseline and follow-up CAC scans approximately 2.5 ± 0.8 years apart; multiple imputation was used to account for the remainder (n=1,096) missing follow-up scans. Median follow-up duration from the baseline was 7.6 (max=9.0) years. CAC change was assessed by absolute change between baseline and follow-up CAC. Cox proportional hazards regression providing hazard ratios (HR) examined the relation of change in CAC with CHD events, adjusting for age, gender, ethnicity, baseline calcium score, and other risk factors. 343 total and 206 hard CHD events occurred. The annual change in CAC averaged 24.9 ± 65.3 units. Among persons without CAC at baseline (n=3,396), a 5 unit annual change in CAC was associated with an adjusted HR of 1.4 (1.0–1.9) for total and 1.5 (1.1–2.1) for hard CHD. Among those with CAC>0 at baseline HR’s (per 100 unit annual change) were 1.2 (1.1–1.4) and 1.3 (1.1–1.5), respectively. Among participants with baseline CAC, those with annual progression of ≥300 units had adjusted HR’s of 3.8 (1.5–9.6) for total and 6.3 (1.9–21.5) for hard CHD compared to those without progression.
Progression of CAC is associated with an increased risk for future hard and total CHD events.
PMCID: PMC4148074  PMID: 23500326
coronary calcification; atherosclerosis; imaging; coronary heart disease
21.  Long-term predictive value of the Framingham Risk Score for Stroke in HIV-positive vs HIV-negative men 
Neurology  2013;81(24):2094-2102.
To test the predictive accuracy of the Framingham Risk Score for Stroke (FRS-S) in HIV-infected (HIV+) vs HIV-uninfected (HIV−) men.
The Multicenter AIDS Cohort Study (MACS) is an ongoing prospective study of HIV+ and HIV− men who have sex with men (MSM) enrolled in 4 US cities. We ascertained all reported stroke events during a recent 15-year timeframe (July 1, 1996 to June 30, 2011) among 3,945 participants (1,776 HIV+ and 2,169 HIV−). For those with strokes, FRS-S were calculated 10 years before the stroke event and assessed according to HIV status.
A total of 114 stroke events occurred, including 57 HIV+ and 37 HIV− participants with first-ever strokes and 19 fatal strokes. The incidence of first-ever stroke was 1.7/1,000 person-years among HIV− and 3.3/1,000 person-years among HIV+ participants. Among those with strokes, HIV+ participants were younger than HIV− participants (median age 51.3 vs 61.8 years, p < 0.0001). For these men with stroke, the average 10-year risk of stroke was higher for HIV− MSM (6.6% [range 3%–26%] vs 4.9% for HIV+ MSM [range 0%–15%], p < 0.04). Traditional risk factors for stroke were similar among the Framingham cohort and the MACS HIV+ and HIV− participants.
FRS-S prediction was systematically different in HIV+ vs HIV− men with stroke events. The FRS-S underestimates the long-term risk of stroke in HIV+ men.
PMCID: PMC3863354  PMID: 24212385
22.  Determinants of Coronary Artery and Aortic Calcification in the Old Order Amish 
Circulation  2007;115(6):717-724.
Coronary artery calcification (CAC) is associated with an increased risk of cardiovascular disease; little is known, however, about thoracic aortic calcification (AC). Our goal was to characterize risk factors for CAC and AC and to estimate the genetic contribution to their variation.
Methods and Results
The presence and quantity of CAC and AC were measured with electron beam computed tomography and fasting blood tests and cardiovascular risk factors were obtained in 614 asymptomatic Amish subjects. CAC prevalence was higher in men than women (55% versus 41%; P<0.0001), although there was no sex difference in AC prevalence (51% and 56% in men and women, respectively; P=0.95). Age was more strongly associated with AC presence (odds ratio [OR], 2.7 for 5 years) than CAC presence (OR, 1.9 for 5 years) (homogeneity P=0.001). Subjects with AC had a 3.3-fold higher odds of having CAC. Heritabilities of CAC and AC presence were 0.27±0.17 (P=0.04) and 0.55±0.18 (P=0.0008), respectively, whereas the heritabilities of quantity of CAC and AC were 0.30±0.10 (P=0.001) and 0.40±0.10 (P<0.0001), respectively. The genetic correlation between CAC and AC quantity was 0.34±0.19, whereas the environmental correlation between these 2 traits was 0.38±0.09.
CAC and AC have similar risk factors, except male gender is associated only with CAC and age is more strongly associated with AC. The patterns of correlations suggest that CAC and AC share some common sets of genes and environmental factors, although it is likely that separate genes and environmental factors also influence calcification at each site.
PMCID: PMC4039563  PMID: 17261661
aging; aorta; atherosclerosis; coronary disease; epidemiology; genetics; imaging
23.  Methods for Estimation of Disparities in Medication Use in an Observational Cohort Study: Results from the Multi-Ethnic Study of Atherosclerosis 
Evaluating disparities in health care is an important aspect of understanding differences in disease risk. The purpose of this study is to describe methodology for estimating such disparities, with application to a large multi-ethnic cohort study.
The Multi-Ethnic Study of Atherosclerosis (MESA) includes 6814 participants aged 45–84 years free of cardiovascular disease. Prevalence ratio (PR) regression was used to model baseline lipid lowering medication (LLM) or anti-hypertensive medication use at baseline as a function of gender, race, risk factors and estimated pre-treatment biomarker values.
Hispanics and African-Americans had lower prevalence of medication use than non-Hispanic whites, even at the same risk factor profile. This became non-significant after adjustment for socio-economic status. Although gender did not influence the prevalence of LLM use (PR=1.09, 95% CI 0.95 to 1.25), there were differences in the association of diabetes and HDL with LLM use by gender. Men were significantly less likely to be on anti-hypertensive medications than women (PR=0.86, 95% CI 0.80 to 0.92, p<0.001) and this was not explained by risk factors or socioeconomic status. Lack of health insurance strongly influenced medication use, controlling for risk factors and other markers of socio-economic status.
Disparities exist in the treatment of cholesterol and hypertension. Hispanics and African Americans had less use of LLM, men had less use of anti-hypertensives. Risk factors have differential associations with medication use depending on gender. Methods described in this paper can provide improved disparity estimation in observational cohort studies.
PMCID: PMC3652567  PMID: 23382107
disparities; medication; statistical methods; statins; anti-hypertensives
24.  Ten-Year Trends in Coronary Calcification in Individuals without Clinical Cardiovascular Disease in the Multi-Ethnic Study of Atherosclerosis 
PLoS ONE  2014;9(4):e94916.
Coronary heart disease (CHD) incidence has declined significantly in the US, as have levels of major coronary risk factors, including LDL-cholesterol, hypertension and smoking, but whether trends in subclinical atherosclerosis mirror these trends is not known.
Methods and Findings
To describe recent secular trends in subclinical atherosclerosis as measured by serial evaluations of coronary artery calcification (CAC) prevalence in a population over 10 years, we measured CAC using computed tomography (CT) and CHD risk factors in five serial cross-sectional samples of men and women from four race/ethnic groups, aged 55–84 and without clinical cardiovascular disease, who were members of Multi-Ethnic Study of Atherosclerosis (MESA) cohort from 2000 to 2012. Sample sizes ranged from 1062 to 4837. After adjusting for age, gender, and CT scanner, the prevalence of CAC increased across exams among African Americans, whose prevalence of CAC was 52.4% in 2000–02, 50.4% in 2003–04, 60.0% is 2005–06, 57.4% in 2007–08, and 61.3% in 2010–12 (p for trend <0.001). The trend was strongest among African Americans aged 55–64 [prevalence ratio for 2010–12 vs. 2000–02, 1.59 (95% confidence interval 1.06, 2.39); p = 0.005 for trend across exams]. There were no consistent trends in any other ethnic group. Risk factors generally improved in the cohort, and adjustment for risk factors did not change trends in CAC prevalence.
There was a significant secular trend towards increased prevalence of CAC over 10 years among African Americans and no change in three other ethnic groups. Trends did not reflect concurrent general improvement in risk factors. The trend towards a higher prevalence of CAC in African Americans suggests that CHD risk in this population is not improving relative to other groups.
PMCID: PMC3990562  PMID: 24743658
25.  Genetic variants associated with VLDL, LDL and HDL particle size differ with race/ethnicity 
Human genetics  2012;132(4):405-413.
Specific constellations of lipoprotein particle features, reflected as differences in mean lipoprotein particle diameters, are associated with risk of insulin resistance (IR) and cardiovascular disease (CVD). The associations of lipid profiles with disease risk differ by race/ethnicity, the reason for this is not clear. We aimed to examine whether there were additional genetic differences between racial / ethnic groups on lipoprotein profile.
Methods and results
Genotypes were assessed using the Affymetrix 6.0 array in 817 related Caucasian participants of the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN). Association analysis was conducted on fasting mean particle diameters using linear models, adjusted for age, sex and study center as fixed effects, and pedigree as a random effect. Replication of associations reaching P<1.97 * 10−05 (the level at which we achieved at least 80% power to replicate SNP-phenotype associations) was conducted in the Caucasian population of the Multi-Ethnic Study of Atherosclerosis (MESA; N=2430). Variants which replicated across both Caucasian populations were subsequently tested for association in the African-American (N=1594), Chinese (N=758) and Hispanic (N=1422) populations of MESA. Variants in the APOB gene region were significantly associated with mean VLDL diameter in GOLDN, and in the Caucasian and Hispanic populations of MESA, while variation in the hepatic lipase (LIPC) gene was associated with mean HDL diameter in both Caucasians populations only.
Our findings suggest the genetic underpinnings of mean lipoprotein diameter differ by race/ethnicity. As lipoprotein diameters are modifiable, this may lead new strategies to modify lipoprotein profiles during the reduction of IR that are sensitive to race / ethnicity.
PMCID: PMC3600091  PMID: 23263444
Lipoprotein size; race / ethnicity; ApoB; Hepatic Lipase; NMR

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