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Introduction: Markers of systemic and vascular inflammation have been associated with cerebral small vessel disease (cSVD). However, their association with cSVD lesions within individual white matter regions remains unclear. We hypothesized that there are different associations of serum cytokines with the periventricular white matter hyperintensity (PVWMH) and deep WMH (DWMH). Methods: Apparently healthy participants aged ≥50 years with brain MRI in the Genetic Study of Atherosclerosis Risk were studied. Circulating inflammatory markers measured included: hs-CRP, IL-6, MCP1, ICAM, TNF-α, VCAM and IL-4. The relative association of these markers with PVWMH and DWMH within individuals were determined using multilevel linear models adjusted for age and cardiovascular risk factors. Results: A total of 435 subjects (age 58.9±6.1 years, 58.4% female, 39.5% black) with moderate WMH burden were studied (Total WMH: 1703[607-4626] mm 3 , PVWMH :871[152-2593] mm 3 , DWMH: 388[157-1023] mm 3 ). Significant negative associations of total WMH volumes and hs-CRP (β=-0.2, P=0.04) as well as IL-6 (β=-0.15, p=0.04) were observed. The associations of total WMH with MCP-1, ICAM, VCAM, IL-4 and TNF-α were not significant. In the multilevel models, designed to compare difference between DWMH and PVWMH within individuals, there were significant differences in the relative association of PVWMH vs DWMH with hs-CRP and IL-6 (p=0.001 & p=0.04, respectively). DWMH was more strongly associated with hs-CRP and IL-6 (β=0.08, β=0.14, respectively) than PVWMH, which had negative association with these markers (β=-0.35, β=-0.05, respectively). There were no differences in the association of PVWMH vs DWMH and the other markers. Conclusions: DWMH is positively associated with increasing IL-6 and CRP when compared to PVWMH which is negatively associated with them. This suggests that systemic inflammation is more preferentially associated with DWMH lesions.

Introduction: We have demonstrated that asymptomatic cerebral small vessel disease (cSVD) measured by white matter hyperintensity volume is associated with reduced manipulative manual dexterity on the Grooved Peg Board Test (GPBT) in middle-aged healthy individuals with a family history of early coronary artery disease. In this current study, we aim to identify the association of subcortical white matter microstructural impairment measured by diffusion tensor imaging, manual dexterity measured by GPBT and circulating serums ceramide, another marker for white matter injury. We hypothesize that lower regional fractional anisotropy (rFA) is associated with worse performance on GPBT and elevated serum ceramides in the same study population. Methods: rFA of 48 regions representing the subcortical white matters were analyzed in GeneSTAR participants in addition to serum ceramides and GPBT scores. Unadjusted univariable analyses with Bonferroni correction for multiple comparisons were completed using Spearman correlation for testing the associations between ceramides, rFA of subcortical white matter, and GPBT performance. Subsequently, sensitivity analyses were performed after excluding the participants that had any physical limitation that may influence their performance on GPBT. Finally, in the adjusted analysis using generalized estimating equation, linear regression models were performed for the areas that met significance threshold in the unadjusted analyses. Results: 112 subjects (age [49 ± 11], 51% female, 39.3% African American) were included. Adjusted analyses for the significant correlations that met the Bonferroni correction threshold in the unadjusted univariable analyses identified significant negative associations between rFA of the right fornix (RF) and log-GPBT score (β = −0.497, p = 0.037). In addition, rFA of RF negatively correlated with log serum ceramide levels (C18: β = −0.03, p = 0.003, C20: β = −0.0002, p = 0.004) and rFA of left genu of corpus callosum negatively correlated with log C18 level (β = −0.0103, p = 0.027). Conclusions: These results demonstrate that subcortical microstructural white matter disruption is associated with elevated serum ceramides and reduced manual dexterity in a population with cSVD. These findings suggest that injury to white matter tracts undermines neural networks, with functional consequences in a middle-aged population with cardiovascular risk factors.

Introduction: The periventricular white matter is more sensitive to alterations in the hemodynamics of the systemic circulation than the deep white matter due to differences in its vascular supply and relationship to systemic circulation. We hypothesize that periventricular white matter hyperintensity volume (PVWMH) shows greater association than deep white matter hyperintensity (DWMH) volume with vascular property measures of arterial stiffness (AS) and cardiovascular remodeling, important indicators of the systemic circulation. Methods: Participants in the Genetic Study of Atherosclerosis Risk ≥ 50 years of age with brain MRI were selected. Vascular property measures included pulse pressure (PP), hypertension response to exercise (HRE), diastolic brachial artery (BA) diameter, diastolic common carotid artery (CCA) diameter, CCA distensibility coefficient, and left ventricular function. PVWMH and DWMH were measured using semi-automated segmentation approach. The relative associations of these parameters with PVWMH and DWMH volumes as multiple measures within the same individual further nested within families were determined using multilevel linear models. We also determined if differences between PVWMH and DWMH associations were modified by age. Results: 426 participants (age 59.0±6.1 years, 57.5% females, and 39.7% African American) were included. Within the same subject, PVWMH volume showed greater association than DWMH volume with PP (P=0.002), HRE (p=0.04), diastolic BA diameter (p=0.012), and diastolic CCA diameter (p=0.04) independent of age and cardiovascular risk factors. This difference in PVWMH versus DWMH association with vascular properties did not differ at any age threshold. Conclusions: We show for the first time that PVWMH volume has greater association than DWMH volume, independent of age, with vascular property measurements of AS and cardiovascular remodeling. Our findings suggest that changes in the systemic circulation may affect PVWMH and DWMH differently adding to a growing body of literature that PVWMH and DWMH may represent different phenotypes of cerebral small vessel disease.

Introduction: White matter hyperintensity (WMH) has been associated with manual dexterity performance in apparently healthy middle-aged population. However, the relative effect of WMH topographic distribution on cognition remains unknown. We hypothesized that periventricular WMH (PVWMH) is more strongly associated with manual dexterity and cognitive measures compared to deep WMH (DWMH) given its proximity to the white matter tracts involved in motor and executive functions. Methods: Apparently healthy middle-aged participants in the Genetic Study of Atherosclerosis Risk with brain MRI and cognitive measurements were selected. Cognitive measures included delayed word recall short (DWRS) and long (DWRL), digit symbol substitution (DSS), word fluency (WF), digit span forward test (DSFT), backward (DSBT) and total (DSTS), and grooved peg board test (GPBT) including the dominant and non-dominant hand (GPBTD, GPBTnD). PVWMH and DWMH volumes were measured using semi-automated segmentation paradigm. The relative associations of these measurements with PVWMH and DWMH volumes as multiple measurements within the same individual further nested within families were determined using multilevel linear models adjusting for intracranial volume, age, sex and cardiovascular risk factors. Results: 782 subjects were included (age 51.1±10.6, 58.4% female and 39% African American, PVWMH volume 437.4 [0-1646] mm 3 , DWMH volume 273.5 [76-665] mm 3 ). Within the same subject, PVWMH showed greater association than DWMH with worse performance on GPBT, GPBTD, GPBTnD, DWRS, and DWRL (P=0.006, 0.01, 0.01, 0.01 and 0.03, respectively) after adjusting for age and other cardiovascular risk factors. There was no difference in the association of PVWMH versus DWMH volumes with DSS, WF, DSFT, DSBT, DSTS (P=0.19, 0.52, 0.13, 0.6, and 0.6, respectively). Conclusions: PVWMH shows greater association than DWMH with cognitive measures of manipulative manual dexterity and recall suggesting that PVWMH and DWMH may have different cognitive phenotypes in middle-aged population with cerebral small vessel disease.

Large-scale whole-genome sequencing studies have enabled analysis of noncoding rare variants’ (RVs) associations with complex human traits. Variant set analysis is a powerful approach to study RV association, and a key component of it is constructing RV sets for analysis. However, existing methods have limited ability to define analysis units in the noncoding genome. Furthermore, there is a lack of robust pipelines for comprehensive and scalable noncoding RV association analysis. Here we propose a computationally-efficient noncoding RV association-detection framework that uses STAAR (variant-set test for association using annotation information) to group noncoding variants in gene-centric analysis based on functional categories. We also propose SCANG (scan the genome)-STAAR, which uses dynamic window sizes and incorporates multiple functional annotations, in a non-gene-centric analysis. We furthermore develop STAARpipeline to perform flexible noncoding RV association analysis, including gene-centric analysis as well as fixed-window-based and dynamic-window-based non-gene-centric analysis. We apply STAARpipeline to identify noncoding RV sets associated with four quantitative lipid traits in 21,015 discovery samples from the Trans-Omics for Precision Medicine (TOPMed) program and replicate several noncoding RV associations in an additional 9,123 TOPMed samples.

Plasma lipids are heritable modifiable causal factors for coronary artery disease, the leading cause of death globally. Despite the well-described monogenic and polygenic bases of dyslipidemia, limitations remain in discovery of lipid-associated alleles using whole genome sequencing, partly due to limited sample sizes, ancestral diversity, and interpretation of potential clinical significance. Increasingly larger whole genome sequence datasets with plasma lipids coupled with methodologic advances enable us to more fully catalog the allelic spectrum for lipids. Here, among 66,329 ancestrally diverse (56% non-European ancestry) participants, we associate 428M variants from deep-coverage whole genome sequences with plasma lipids. Approximately 400M of these variants were not studied in prior lipids genetic analyses. We find multiple lipid-related genes strongly associated with plasma lipids through analysis of common and rare coding variants. We additionally discover several significantly associated rare non-coding variants largely at Mendelian lipid genes. Notably, we detect rareLDLRintronic variants associated with markedly increased LDL-C, similar to rareLDLRexonic variants. In conclusion, we conducted a systematic whole genome scan for plasma lipids expanding the alleles linked to lipids for multiple ancestries and characterize a clinically-relevant rare non-coding variant model for lipids.

Blood lipids are heritable modifiable causal factors for coronary artery disease. Despite well-described monogenic and polygenic bases of dyslipidemia, limitations remain in discovery of lipid-associated alleles using whole genome sequencing (WGS), partly due to limited sample sizes, ancestral diversity, and interpretation of clinical significance. Among 66,329 ancestrally diverse (56% non-European) participants, we associate 428M variants from deep-coverage WGS with lipid levels; ~400M variants were not assessed in prior lipids genetic analyses. We find multiple lipid-related genes strongly associated with blood lipids through analysis of common and rare coding variants. We discover several associated rare non-coding variants, largely at Mendelian lipid genes. Notably, we observe rare LDLR intronic variants associated with markedly increased LDL-C, similar to rare LDLR exonic variants. In conclusion, we conducted a systematic whole genome scan for blood lipids expanding the alleles linked to lipids for multiple ancestries and characterize a clinically-relevant rare non-coding variant model for lipids.

Background and Purpose: We aim to determine, in healthy high-risk adults, the association between subclinical coronary artery disease and white matter hyperintensity (WMH) volume and location, independent of atherosclerotic risk factors. Methods: Seven hundred eighty-two asymptomatic first-degree relatives of index cases with early-onset coronary artery disease ( Results: Mean age was 51 years ±10, with 58% women and 39% African American people. Participants with any coronary plaque had 52% larger WMH volumes than those without plaque (95% CI, 0.24–0.59). Per 1% greater coronary plaque volume, total WMH volumes were 0.07% larger (95% CI, 0.04–0.10). Every 1% higher total coronary plaque volume was associated with 5.03% larger deep WMH volume (95% CI, 4.67–5.38), 5.10% PVWMH larger volume (95% CI, 4.72–5.48), and 2.74% larger cuff volume (95% CI, 2.38–3.09) with differences in this association when comparing deep WMH to PVWMH ( P interaction, 0.001) or cuff ( P interaction, Conclusions: In healthy, high-risk individuals, the presence and volume of coronary artery plaque are associated with larger WMH volumes, appearing the strongest for PVWMH. These findings in high-risk families suggest a disease relationship in 2 different vascular beds, beyond traditional risk factors, possibly due to genetic predisposition.

Introduction: Induced pluripotent stem cells (iPSC) have a significant capacity for self-renewal and can differentiate into any somatic cell type, such as megakaryocytes (MK) and vascular endothelial cells (EC). We have previously shown that iPSC-derived MKs (IPSC-MK) upregulate the gene expression levels of irreversible glycolytic enzymes committing glucose to glycolysis in comparison to their parental iPSC lines (Vaidya et al., 2016). This pattern differed from past comparisons between somatic source cells and iPSCs (Chung et al., 2007; Varum et al., 2011; Zhang et al., 2011). To further corroborate our data, we extended our analysis to iPSC-derived ECs (iPSC-EC). Methods: We studied expression of glycolytic enzyme genes in 30 human iPSC lines and paired iPSC-EC and iPSC-MK lines using RNA-seq. iPSC-EC to iPSC expression ratios for 11 glycolytic enzymes were estimated using a multilevel mixed-effect model regression, and a significance threshold of p < 0.05/11 = 0.0045 was used. A bivariate statistical analysis was used to assess the correlation between iPSC-EC and iPSC-MK data. Results: Of the 11 glycolytic enzymes studied, 4 were highly expressed in iPSC-ECs (Log2(iPSC-EC/iPSC) ≥ 1) while 1 was highly expressed in iPSCs (Log2(iPSC/iPSC-EC) ≥ 1). Transcripts for functionally irreversible enzymes including ADPGK, PFKP, and PKLR displayed higher expression levels in iPSC-ECs compared to iPSCs. Similarly, 6 glycolytic genes demonstrated higher expression in iPSC-MKs, while 2 were more highly expressed in iPSCs. The functionally irreversible enzymes HK1, ADPGK, and PFK exhibited higher expression levels in iPSC-MKs. The ratios of gene expression (derived-lines:iPSCs) for all 37 genes in the iPSC-MK results correlated with those of the iPSC-EC results: Pearson’s r = 0.52, p = 0.001. Conclusion: Both iPSC-ECs and iPSC-MKs upregulate the expression of glycolytic enzymes compared to their parental iPSCs. In light of data showing that differentiated cells are more metabolically active and have more mitochondria than iPSCs (Chandra et al., 2020), these results suggest that differentiation of iPSCs is accompanied by an increase in both glycolytic and TCA cycle activities, with glycolytic generation of pyruvate used for mitochondrial production of ATP.

Background and Purpose: Periventricular white matter hyperintensities (WMH; PVWMH) and deep WMH (DWMH) are regional classifications of WMH and reflect proposed differences in cause. In the first study, to date, we undertook genome-wide association analyses of DWMH and PVWMH to show that these phenotypes have different genetic underpinnings. Methods: Participants were aged 45 years and older, free of stroke and dementia. We conducted genome-wide association analyses of PVWMH and DWMH in 26,654 participants from CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology), ENIGMA (Enhancing Neuro-Imaging Genetics Through Meta-Analysis), and the UKB (UK Biobank). Regional correlations were investigated using the genome-wide association analyses -pairwise method. Cross-trait genetic correlations between PVWMH, DWMH, stroke, and dementia were estimated using LDSC. Results: In the discovery and replication analysis, for PVWMH only, we found associations on chromosomes 2 ( NBEAL ), 10q23.1 ( TSPAN14/FAM231A ), and 10q24.33 ( SH3PXD2A). In the much larger combined meta-analysis of all cohorts, we identified ten significant regions for PVWMH: chromosomes 2 (3 regions), 6, 7, 10 (2 regions), 13, 16, and 17q23.1. New loci of interest include 7q36.1 ( NOS3 ) and 16q24.2. In both the discovery/replication and combined analysis, we found genome-wide significant associations for the 17q25.1 locus for both DWMH and PVWMH. Using gene-based association analysis, 19 genes across all regions were identified for PVWMH only, including the new genes: CALCRL (2q32.1), KLHL24 (3q27.1), VCAN (5q27.1), and POLR2F (22q13.1). Thirteen genes in the 17q25.1 locus were significant for both phenotypes. More extensive genetic correlations were observed for PVWMH with small vessel ischemic stroke. There were no associations with dementia for either phenotype. Conclusions: Our study confirms these phenotypes have distinct and also shared genetic architectures. Genetic analyses indicated PVWMH was more associated with ischemic stroke whilst DWMH loci were implicated in vascular, astrocyte, and neuronal function. Our study confirms these phenotypes are distinct neuroimaging classifications and identifies new candidate genes associated with PVWMH only.

Background: Whether obesity in the absence of cardiometabolic abnormalities increases the risk of subclinical atherosclerosis remains debatable. Methods: We compared coronary artery calcium (CAC) across obesity phenotypes in 505 Whites and 306 African Americans (AAs) from the Genetic Study of Aspirin Responsiveness (GeneSTAR); and 875 South Asians (SAs) from MASALA (Mediators of Atherosclerosis in South Asians Living in America). Using BMI and the International Harmonized Definition of metabolic syndrome, participants were categorized as Metabolically Healthy Non-Obese (MHNO), Metabolically Healthy Obese (MHO), Metabolically Unhealthy Non-Obese (MUNO), and Metabolically Unhealthy Obese (MUO). Results: The prevalence of any detectable CAC was similar in MHNO versus MHO among all ethnic groups (Whites 35 versus 30%, AAs 30 versus 23%, SAs 29 versus 26%; respectively, all p>0.05). In contrast, the prevalence of CAC was the highest in the MUNO and MUO groups in all ethnic groups. After adjusting for potential confounders; the odds of CAC in MUNO and MUO compared to MHNO were significantly higher in Whites and SAs; but not in AAs. Conclusion: Metabolically unhealthy Whites, AAs, and SAs had higher CAC scores regardless of obesity status suggesting that metabolic health is more closely associated with atherosclerosis than obesity alone especially in Whites and SAs. Disclosure M. Al-Sofiani: Speaker’s Bureau; Self; Novo Nordisk Inc. D. Vaidya: None. A.M. Kanaya: None. L. Yanek: None. M. Mongraw-Chaffin: None. N.R. Kandula: None. L. Becker: None. B.G. Kral: None. D. Becker: None. N.M. Maruthur: Other Relationship; Self; Johns Hopkins HealthCare Solutions. C. Lee: Employee; Self; Eli Lilly and Company. Funding National Institutes of Health (R01HL093009, K24HL112827); National Center for Research Resources (UL1RR024131, M01-RR000052); National Heart, Lung, and Blood Institute (U01HL72518)

Introduction: We previously reported impaired manipulative manual dexterity measured by grooved peg-board test (GPBT) in healthypeople with increased total brain ischemic white matter hyperintensities. We hypothesized that preclinical white matter tract damage (WMTD), measured as lower regional fractional anisotropy (rFA), is associated with functional decrements measured with GPBT, and with a biomarker of white matter disease, serum ceramides. Methods: Participants were recruited from the GeneSTAR study in families with a history of coronary artery disease. Diffusion tensor imaging was acquired on a Phillips 3T MRI and rFA was calculated using the 181 Eve segmented atlas. 48 susceptible regions for WMTD were analyzed.Liquid chromatography was used to measure ceramides (C). Spearman’s rank correlation (SRC) was used to test statistical associations and Bonferroni method was used to correct for multiple comparisons. Multivariate analysis (GEE) adjusting for age, sex, race and education was performed for associations that were significant in the univariate analyses. Result: Subjects (n=112) were 49±11 years; 49% male and 39% African American. rFA was correlated with decrements on GPBT in the left (L) anterior corona radiata, L genu of the corpus callosum (LGCC), L external capsule, and L & right fornix (RF) (P=0.0009, 0.0008, 0.0002, 0.0003 and 8.2E-07, respectively). Additionally, rFA was negatively correlated with C18:0 in the RF and LGCC (P=1.27E-05 and 2.58E-05, respectively) and C20:0 in RF (P=6.09E-06). C18:0 was correlated with decrements on GPBT (P=0.0025). GEE showed associations between decremental GPBT and rFA in the RF (B = -0.52, 95% CI -1 - 0.03, p= 0.037), between rFA in the RF and Ceramide (C18:0, B= -0.03, 95% CI -0.046--0.0073, p=0.007, C20:0, B=-0.0002, 95%CI -0.0003-0, P= 0.018), as well as rFA in LGCC and Ceramide (C18:0, B=-0.0097, 95% CI -0.019--0.006, P=0.037). GBPT and ceramides were not associated when adjusted for rFA (B = 0.0002 95% CI -0.052 - 0.052 P= 0.99). Conclusion: These analyses support our hypothesis that preclinical WMTD represented by reduced rFA, may undermine neural networks affecting manipulative manual dexterity, with concomitant elevation in serum ceramides in healthy high risk people.

Background Genome-wide association studies have identified multiple genomic loci associated with coronary artery disease, but most are common variants in non-coding regions that provide limited information on causal genes and etiology of the disease. To overcome the limited scope that common variants provide, we focused our investigation on low-frequency and rare sequence variations primarily residing in coding regions of the genome. Methods and results Using samples of individuals of European ancestry from ten cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, both cross-sectional and prospective analyses were conducted to examine associations between genetic variants and myocardial infarction (MI), coronary heart disease (CHD), and all-cause mortality following these events. For prevalent events, a total of 27,349 participants of European ancestry, including 1831 prevalent MI cases and 2518 prevalent CHD cases were used. For incident cases, a total of 55,736 participants of European ancestry were included (3,031 incident MI cases and 5,425 incident CHD cases). There were 1,860 all-cause deaths among the 3,751 MI and CHD cases from six cohorts that contributed to the analysis of all-cause mortality. Single variant and gene-based analyses were performed separately in each cohort and then meta-analyzed for each outcome. A low-frequency intronic variant (rs988583) in PLCL1 was significantly associated with prevalent MI (OR = 1.80, 95% confidence interval: 1.43, 2.27; P = 7.12 × 10−7). We conducted gene-based burden tests for genes with a cumulative minor allele count (cMAC) ≥ 5 and variants with minor allele frequency (MAF) < 5%. TMPRSS5 and LDLRAD1 were significantly associated with prevalent MI and CHD, respectively, and RC3H2 and ANGPTL4 were significantly associated with incident MI and CHD, respectively. No loci were significantly associated with all-cause mortality following a MI or CHD event. Conclusion This study identified one known locus (ANGPTL4) and four new loci (PLCL1, RC3H2, TMPRSS5, and LDLRAD1) associated with cardiovascular disease risk that warrant further investigation.

BACKGROUND AND PURPOSE: Traditional cardiovascular risk factors have been associated with white matter disease. Because hypertension results in vascular stiffness and impaired cerebral perfusion, we hypothesized that it would be the most relevant risk factor for microstructural white matter disruption in apparently healthy middle-aged individuals with a family history of early-onset coronary artery disease. MATERIALS AND METHODS: This was a cross-sectional analysis of participants in the Genetic Study of Atherosclerosis Risk with DTI. Regional fractional anisotropy of 181 segmented brain regions was measured using Eve WM Atlas. Risk factors were examined using univariate analysis for 48 regions representing deep WM structures. Minimal multivariable linear regression models adjusting for age, sex, and race and maximal linear regression models adjusting for cardiovascular risk factors were performed for regions meeting the Bonferroni threshold in the initial analysis. RESULTS: Included were 116 subjects (mean age, 49 ± 11 years; 57% men) with a moderate load of cardiovascular risk factors. Subjects with hypertension had significantly lower regional fractional anisotropy in the right cingulum and left stria terminalis in the minimal and maximal regression models. Additionally, there was lower regional fractional anisotropy in the left fornix in the maximal model and right sagittal stratum in the minimal model. Systolic blood pressure values were significantly associated with regional fractional anisotropy in the left superior longitudinal fasciculus in the maximal model. There were no significant differences among regional fractional anisotropy values for other cardiovascular risk factors. CONCLUSIONS: In middle-aged apparently healthy individuals with susceptibility to vascular disease, among all known cardiovascular risk factors, hypertension was associated with microstructural WM disruption.

Polychromatic flow cytometry is a useful tool for monitoring circulating whole blood monocytes, although gating strategies often vary depending on the study. Increased analyses of the myeloid system have revealed monocytes to be more plastic than previously understood and uncovered changes among surface markers previously considered to be stable. The myeloid system has also been found to have disparate surface markers between mouse, human, and non-human primate studies, which further complicates examination between species. This study has found bright Toll-like receptor 2 (TLR2) expression to be a consistent surface marker of circulating whole blood monocytes in humans and two species of macaques. Furthermore, within our pigtailed macaque model of HIV-associated CNS disease, where monocyte surface markers have previously been shown to reorganize during acute infection, TLR2 remains stably expressed on the surface of classical, intermediate, and non-classical monocytes. Our findings demonstrate that TLR2 is a useful surface marker for including all monocytes during other phenotypic changes that may alter the expression of common surface receptors. These results provide a practical tool for studying all types of monocytes during inflammation and infection within humans and macaques. © 2017 International Society for Advancement of Cytometry.

Whole-genome sequencing (WGS) can improve assessment of low-frequency and rare variants, particularly in non-European populations that have been underrepresented in existing genomic studies. The genetic determinants of C-reactive protein (CRP), a biomarker of chronic inflammation, have been extensively studied, with existing genome-wide association studies (GWASs) conducted in >200,000 individuals of European ancestry. In order to discover novel loci associated with CRP levels, we examined a multi-ancestry population (n = 23,279) with WGS (∼38× coverage) from the Trans-Omics for Precision Medicine (TOPMed) program. We found evidence for eight distinct associations at the CRP locus, including two variants that have not been identified previously (rs11265259 and rs181704186), both of which are non-coding and more common in individuals of African ancestry (∼10% and ∼1% minor allele frequency, respectively, and rare or monomorphic in 1000 Genomes populations of East Asian, South Asian, and European ancestry). We show that the minor (G) allele of rs181704186 is associated with lower CRP levels and decreased transcriptional activity and protein binding in vitro, providing a plausible molecular mechanism for this African ancestry-specific signal. The individuals homozygous for rs181704186-G have a mean CRP level of 0.23 mg/L, in contrast to individuals heterozygous for rs181704186 with mean CRP of 2.97 mg/L and major allele homozygotes with mean CRP of 4.11 mg/L. This study demonstrates the utility of WGS in multi-ethnic populations to drive discovery of complex trait associations of large effect and to identify functional alleles in noncoding regulatory regions.

We conducted a genome-wide association meta-analysis of two ischemic white matter disease subtypes in the brain, periventricular and deep white matter hyperintensities (PVWMH and DWMH). In 26,654 participants, we found 10 independent genome-wide significant loci only associated with PVWMH, four of which have not been described previously for total WMH burden (16q24.2, 17q21.31, 10q23.1, 7q36.1). Additionally, in both PVWMH and DWMH we observed the previous association of the 17q25.1 locus with total WMH. We found that both phenotypes have shared but also distinct genetic architectures, consistent with both different underlying and related pathophysiology. PVWMH had more extensive genetic overlap with small vessel ischemic stroke, and unique associations with several loci implicated in ischemic stroke. DWMH were characterized by associations with loci previously implicated in vascular as well as astrocytic and neuronal function. Our study confirms the utility of these phenotypes and identifies new candidate genes associated only with PVWMH.

PURPOSE: To compare epicardial fat in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) with that in healthy subjects. MATERIALS AND METHODS: In this retrospective study, cardiac CT scans in 44 patients with ARVD/C (mean age, 39 years ± 12; 23 men) were compared with those in 45 control group participants between January 2008 and July 2015. Volumes of intrathoracic adipose tissue, mediastinal adipose tissue (MAT), and total epicardial adipose tissue (EAT) were quantified. EAT was subdivided into three regions—right ventricular (RV) EAT, left ventricular (LV) EAT, and peri-atrial EAT (atrial EAT)—and normalized to MAT for all regions. Logistic regression and receiver operating characteristic analysis were performed to evaluate the association between epicardial fat with the diagnosis of ARVD/C. RESULTS: Total EAT volume was higher in patients with ARVD/C than in healthy control group participants (median, 98 mL vs 76 mL, respectively; P = .04). Regionally, LV and RV EAT volumes were higher in patients with ARVD/C than in control group participants, most notably when indexed to MAT (median LV EAT index: 0.49 vs 0.15, respectively; median RV EAT index: 0.91 vs 0.52; P ˂ .0005 for both). The optimal cutoff for diagnosis of ARVD/C was an LV EAT index of 0.24, with a sensitivity and specificity of 91% and 71%, respectively. Atrial EAT volume and total intrathoracic adipose tissue volume were not different between groups. RV diameter showed a positive correlation with total EAT index and LV EAT index (r = 0.21, P = .05 and r = 0.33, P = .002, respectively). CONCLUSION: Higher amounts of right ventricular and left ventricular epicardial fat are found in hearts with arrhythmogenic right ventricular dysplasia/cardiomyopathy, particularly adjacent to the left ventricle, which correlates with disease severity and helps differentiate patients from healthy subjects. © RSNA, 2018 Online supplemental material is available for this article.

African Americans have a high prevalence of obesity and physical inactivity, but few interventions have been successful in the long term. We describe a 1-year intervention program to increase physical activity and reduce cardiometabolic risk. Interventions incorporated the premise that self-selection into flexible venues and varying exercise modalities would result in improvement in fitness and risk factors. Results of this single-group pretest/posttest observational study show 1-year overall group reductions in body weight and body mass index and cardiometabolic factors including high-sensitivity C-reactive protein, and increases in dual-energy x-ray absorptiometry-derived absolute and percent lean mass and lean-fat ratio, and decreased fat mass.

Serum lipoprotein(a) [Lp(a)] is a coronary artery disease (CAD) risk factor in persons of European ancestry. Levels are twofold to threefold higher in African-Americans (AAs), but reported associations with CAD have been inconsistent. The relation of Lp(a) with the extent and severity of subclinical coronary plaque has not been described in AAs. We screened 269 apparently healthy AAs for risk factors and coronary plaque using advanced coronary computed tomographic angiography. Total coronary plaque (TCP), noncalcified coronary plaque, and calcified coronary plaque volumes (mm 3 ) were quantified using a validated automated method. Lp(a) was measured by ELISA. Multivariable modeling was performed with adjustment for traditional CAD risk factors and intrafamilial correlations. Mean age was 51 ± 11 years and 64% were female. Plaque was present in 41%. Lp(a) was independently associated with TCP volume [log(TCP + 1)] (p = 0.04), 3-vessel and/or left main involvement (p = 0.04), and at least 1 stenosis >50% (p = 0.006). Best-fit regression analyses showed that subjects with Lp(a) >40 mg/dl were threefold more likely to have 3-vessel and/or left main disease (95% confidence interval 1.4 to 6.8, p = 0.005) and fourfold more likely to have stenosis >50% (95% confidence interval 1.3 to 15.0, p = 0.02). In subjects with plaque (n = 110), multivariable models showed the Lp(a) level was significantly and independently associated with TCP (p = 0.009), noncalcified coronary plaque (p = 0.01), and calcified coronary plaque (p = 0.003) and affected vessel length (p = 0.01). In conclusion, high Lp(a) is strongly associated with coronary plaque volumes, extent, and severity in apparently healthy AAs. High levels of Lp(a) may be particularly important in the pathogenesis of CAD in AAs.

Background— The burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease. We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent coronary heart disease. Methods and Results— We studied a total of 25 109 European ancestry and African ancestry participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52 869 participants with common carotid intima–media thickness measured by ultrasonography within the CHARGE Consortium (Cohorts for Heart and Aging Research in Genomic Epidemiology). Participants were genotyped for 247 870 DNA sequence variants (231 539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and carotid intima–media thickness. APOB p.Arg3527Gln was associated with 4-fold excess CAC ( P =3×10 − 10 ). The APOE ε2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC ( P =1×10 − 12 ) and 1.4% reduced carotid intima–media thickness ( P =4×10 − 14 ) in carriers compared with noncarriers. In secondary analyses conditioning on low-density lipoprotein cholesterol concentration, the ε2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of ε2 was associated with reduced risk for coronary heart disease (odds ratio 0.77; P =1×10 − 11 ). Conclusions— Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE ε2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities, as well as clinical coronary heart disease.

CONTEXT: Previous studies have suggested less cardioprotective benefit of aspirin in adults with diabetes, raising concerns about “aspirin resistance” and potentially reduced effectiveness for prevention of cardiovascular disease (CVD). OBJECTIVE: To examine differences in platelet response to aspirin by diabetes status. DESIGN, SETTING, PARTICIPANTS: We examined platelet response before and after aspirin (81 mg/day for 14 days) in 2113 adults (175 with diabetes, 1,938 without diabetes), in the Genetic Study of Aspirin Responsiveness cohort, who had family history of early-onset CVD. MAIN OUTCOME MEASURES: In vivo platelet activation (urinary thromboxane B2), in vitro platelet aggregation to agonists (arachidonic acid, adenosine diphosphate, collagen), and platelet function analyzer-100 closure time. RESULTS: Although adults with diabetes had higher in vivo platelet activation before aspirin, the reduction in in vivo platelet activation after aspirin was similar in those with vs without diabetes. Likewise, the reduction in multiple in vitro platelet measures was similar after aspirin by diabetes status. In regression analyses adjusted for age, sex, race, BMI, smoking, platelet counts, and fibrinogen levels, in vivo platelet activation remained higher in adults with vs without diabetes after aspirin (P = 0.04), but this difference was attenuated after additional adjustment for preaspirin levels (P = 0.10). No differences by diabetes status were noted for any of the in vitro platelet measures after aspirin in fully adjusted models that also accounted for preaspirin levels. CONCLUSIONS: In vitro platelet response to aspirin does not differ by diabetes status, suggesting no intrinsic differences in platelet response to aspirin. Instead, factors extrinsic to platelet function should be investigated to give further insights into aspirin use for primary prevention in diabetes.

Introduction: White matter tract disruption (WMTD) on Diffusion Tensor Imaging (DTI) may reflect early axonal disruption and tract injury and identify risk for dementia. Brain ceramides play a role in processes also associated with dementia risk. We hypothesized that circulating ceramide levels might serve as biomarkers of WMTD in a population at high risk for early vascular disease. We studied six ceramides and WMTD using fractional anisotropy (FA) on DTI in healthy relatives of patients with early coronary disease. We have previously shown a high prevalence of white matter hyperintensities (WMH) and significant associations between WMH volumes, FA, and lower cognitive function in healthy relatives. Methods: DTI was acquired with Phillips 3T MRI. FA was measured for 181 regions of the segmented brain using Eve atlas. 48 relevant regions with susceptibility for WMTD were analyzed. Serum ceramides were measured using high performance liquid chromatography. Spearman correlations and GEE linear regression analyses (adjusted for age, sex, race, education and family relatedness) were used. We set the significance level to meet the Bonferroni threshold of 0.00017 (0.05 / 48 regions/6 ceramides). Results: Subjects, N=112, had a mean age of 49± 11 years; education 14 ± 3 years; 49% male; 39% African American, 61% European American). Serum levels for ceramides designated C18:0, C20:0, and C22:0 were significantly negatively correlated with FA in the right fornix (C18:0, R=-0.40, p=1.3 x10 -5 , C20:0, R=-0.41, p= 6.1 x 10 -6 , C22:0, R=-0.33, p=4.3 x10 -4 ). C18:0 was negatively correlated with the left genu of corpus callosum (R=-0.39, p=2.6 x10 -5 ) and right body of corpus callosum (R=-0.31, p=8.5 x10 -4 ). An additional ceramide, C24:0, was correlated with both sides of the posterior limb of internal capsule (left R=0.34, p=2.5 x10 -4 ; right R=0.34, p=2.8 x10 -4 ). All ceramide-FA associations were significant (p Conclusions: We show a robust relationship between serum ceramides and WMTD using FA in a middle-aged, cognitively intact at-risk population enriched for early WMH. Thus, serum ceramide levels may reflect subtle alterations in white matter tract microstructure at an early preclinical stage.

Introduction: Cerebrovascular disease (CVD) and vascular risk factors cluster in families of patients with early-onset coronary artery disease (CAD). In a prior cross-sectional study of 714 healthy middle-aged relatives, we found a high prevalence of early white matter hyperintensity lesions (WMHL) and associated lower cognitive function. Prior WMHL studies have included elderly or demented subjects. Rate of WMHL progression and cognitive decline in quiescent preclinical healthy middle-aged persons remains unknown. Methods: We studied WMHL and cognitive function over 5 years in 20 healthy relatives, age 50-59, of patients with CAD Results: Our 20 participants were: 50% male, 45% African American (AA), average age was 54.1 (SD 1.57) years, 45% with HTN, 15% smokers, and 50% obese. WMHL prevalence was 92%. The average change in WMHL volume was 819 mm 3 (P Conclusion: These striking findings are among the first to demonstrate significant quantitative WMHL volume progression and cognitive decline in a healthy middle-aged population over just 5 years, in AA and EA and both sexes. This small pilot study suggests that early quiescent brain white matter lesion progression and early multidimensional cognitive decline can be detected in healthy susceptible populations using state-of-the-art quantitative volumetric imaging techniques.

Type 2 diabetes (T2DM) in a first-degree relative is a risk factor for incident diabetes. Americans of African ancestry (AA) have higher rates of T2DM than Americans of European ancestry (EA). Thus, we aimed to determine whether the presence, number and kinship of affected relatives are associated with race-specific T2DM incidence in a prospective study of participants from the Genetic Study of Atherosclerosis Risk (GeneSTAR), who underwent baseline screening including a detailed family history.Nondiabetic healthy siblings (n=1405) of patients with early-onset coronary artery disease (18-59 years) were enrolled (861 EA and 544 AA) and followed for incident T2DM (mean 14±6 years).Baseline age was 46.2±7.3 years and 56% were female. T2DM occurred in 12.3% of EA and 19.1% of AA. Among EA, 32.6% had ≥1 affected first-degree relatives versus 53.1% in AA, P0.0001. In fully adjusted Cox proportional hazard analyses, any family history was related to incident T2DM in EA (HR=2.53, 95% CI: 1.58-4.06) but not in AA (HR=1.01, 0.67-1.53). The number of affected relatives conferred incremental risk of T2DM in EA with HR=1.82 (1.08-3.06), 4.83 (2.15-10.85) and 8.46 (3.09-23.91) for 1, 2, and ≥3 affected, respectively. In AA only ≥3 affected increased risk (HR=2.45, 1.44-4.19). Specific kinship patterns were associated with incident T2DM in EA but not in AA.The presence of any first-degree relative with T2DM does not discriminate risk in AA given the high race-specific prevalence of diabetes. Accounting for the number of affected relatives may more appropriately estimate risk for incident diabetes in both races.

We hypothesized that integrated motor-visual functions measured by manipulative manual dexterity are affected by white matter lesion (WML) burden as measured on cranial MRI across relevant brain regions in subjects at risk of preclinical occult vascular disease.A real-time cross-sectional study of healthy subjects aged 29 to 74 years with a family history of early-onset coronary artery disease (n = 714; mean age, 51 ± 11 years; mean education, 14 ± 3 years; 42% male; 38% black) were identified from probands with coronary artery disease diagnosed before age 60 years. WMLs on 3-tesla brain MRI and Grooved Pegboard scores were measured.WMLs were observed at all ages. Mean pegboard scores were 108 ± 18, similar to normal populations. In unadjusted analysis, WMLs and pegboard scores were significantly correlated by region (total WMLs, r = 0.34, p = 0.0001; frontal [r = 0.34, p0.0001], insula [r = 0.31, p0.0001], parietal [r = 0.31, p0.0001], and temporal [r = 0.17, p0.0001]). In multivariate analysis predicting (log) pegboard score adjusted for age, sex, race, education, regional or total volumes, and familial non-independence, total WML volume (p = 5.79E - 05) and regional WML volumes (p0.01) retained statistical significance in all but the youngest age quartile (29-43 years).Greater WML volumes in different brain regions are associated with higher pegboard scores (worse performance) independent of age, sex, race, education, and total or regional volumes. This suggests that small vessel cerebrovascular disease may be present in healthy individuals in a preclinical state with measurable impact on complex integrative functions in individuals with excess risk of clinical vascular disease.

Polychromatic flow cytometry is a useful tool for monitoring circulating whole blood monocytes, although gating strategies often vary depending on the study. Increased analyses of the myeloid system have revealed monocytes to be more plastic than previously understood and uncovered changes among surface markers previously considered to be stable. The myeloid system has also been found to have disparate surface markers between mouse, human, and non‐human primate studies, which further complicates examination between species. This study has found bright Toll‐like receptor 2 (TLR2) expression to be a consistent surface marker of circulating whole blood monocytes in humans and two species of macaques. Furthermore, within our pigtailed macaque model of HIV‐associated CNS disease, where monocyte surface markers have previously been shown to reorganize during acute infection, TLR2 remains stably expressed on the surface of classical, intermediate, and non‐classical monocytes. Our findings demonstrate that TLR2 is a useful surface marker for including all monocytes during other phenotypic changes that may alter the expression of common surface receptors. These results provide a practical tool for studying all types of monocytes during inflammation and infection within humans and macaques. © 2017 The Authors. Cytometry Part A Published by Wiley Periodicals, Inc. on behalf of ISAC.

Background: Fractional anisotropy (FA) measured by Diffusion Tensor Imaging (DTI) is a sensitive biomarker of white matter (WM) integrity and offers a means to detect early axonal disruption and attendant cognitive impairment secondary to vascular disease. Hypothesis: We hypothesized that hypertension (HTN), of all known risk factors, is most closely linked to early WM tract injury in apparently healthy high risk relatives of patients with early-onset coronary artery disease (CAD). Methods: DTI was acquired on a Phillips 3T MRI scanner (slice thickness 2.2 mm, field of view 212X212 mm and b-value 700 mm 2 /s) for relatives of CAD patients. The brain was segmented into 181 regions using the Eve Atlas, Large Deformation Diffeomorphic Metric Mapping paradigm, and 48 regions representing the deep WM were selected for analysis. Mean regional FA (rFA) was assessed using t-tests in persons with and without smoking, HTN, diabetes. Continuous variable association with rFA was tested using Spearman correlations. Covariate-adjusted GEE linear regression (corrected for nonindependence of families) was performed for regions meeting the Bonferroni threshold of 0.001 (0.05/48). Results: 116 subjects had DTI data (mean age 49.5±11, 57% males, 40.5% African Americans, 23% smokers, 36% hypertensives, 12% diabetics). rFA was not significantly associated with diabetes or current smoking. Moreover, rFA was not significantly correlated with glucose level, LDL, total cholesterol or body mass index. However, patients with HTN showed a significantly lower rFA compared to normotensives in the left (L) genu of corpus callosum, L external capsule, right (R) cingulum, L fornix/ stria terminalis, L and R column and body of fornix, and R sagittal stratum. After adjusting for age, sex and race, this relation remained significant in the R sagittal stratum (P=0.012) and R cingulum (P=0.001). Systolic blood pressure (SBP) correlated with rFA after adjustment in the L superior longitudinal fasciculus as well (unadjusted rho=-0.309, p=0.00073, adjusted beta =-1.08+-0.47, P=0.02). Conclusions: Of all of the risk factors, as hypothesized, HTN and SBP were significantly associated with early WM tract injury in areas related to cognition in middle-aged persons at risk for vascular disease.

Greater ex vivo platelet aggregation to agonists may identify individuals at risk of acute coronary syndromes (ACS). However, increased aggregation to a specific agonist may be masked by inherent variability in other activation pathways. In this study, we inhibited the cyclooxygenase-1 (COX1) pathway with 2-week aspirin therapy and measured residual aggregation to collagen and ADP to determine whether increased aggregation in a non-COX1 pathway is associated with incident ACS. We assessed ex vivo whole blood platelet aggregation in 1,699 healthy individuals with a family history of early-onset coronary artery disease followed for 6±1.2 years. Incident ACS events were observed in 22 subjects. Baseline aggregation was not associated with ACS. After COX1 pathway inhibition, collagen-induced aggregation was significantly greater in participants with ACS compared with those without (29.0 vs. 23.6 ohms, p < 0.001). In Cox proportional hazards models, this association remained significant after adjusting for traditional cardiovascular risk factors (HR = 1.10, 95%CI = 1.06-1.15; p < 0.001). In contrast, ADP-induced aggregation after COX1 inhibition was not associated with ACS. After COX1 pathway inhibition, subjects with greater collagen-induced platelet aggregation demonstrated a significant excess risk of incident ACS. These data suggest that platelet activation related to collagen may play an important role in the risk of ACS.

Background: African Americans (AAs) have a higher prevalence of extreme ischemic white matter hyperintensities (WMHs) on magnetic resonance imaging (MRI) than do European Americans (EAs) based on the Cardiovascular Health Study (CHS) score. Ischemic white matter disease, limited to the deep white matter, may be biologically distinct from disease in other regions and may reflect a previously observed trend toward an increased risk of subcortical lacunar infarcts in AAs. We hypothesized that extreme deep WMH volume (DWMV) or periventricular volume (PV) may also have a higher prevalence in AAs. Thus, we studied extreme CHS scores and extreme DWMV and PV in a healthy population enriched for cardiovascular disease risk factors. Methods: We imaged the brains of 593 subjects who were first-degree relatives of probands with early onset coronary disease prior to 60 years of age. WMHs were manually delineated on 3-tesla cranial MRI by a trained radiology reader; the location and volume of lesions were characterized using automated software. DWMV and PV were measured directly with automated software, and the CHS score was determined by a neuroradiologist. Volumes were characterized as being in the upper 25% versus lower 75% of total lesion volume. Volumes in the upper versus the remaining quartiles were examined for AA versus EA race using multiple logistic regression (generalized estimating equations adjusted for family relatedness) and adjusted for major vascular disease risk factors including age ≥55 years versus 160 mg/dl. Results: Participants were 58% women and 37% AAs, with a mean age of 51.5 ± 11.0 years (range, 29-74 years). AAs had significantly higher odds of having extreme DWMVs (odds ratio, OR, 1.8; 95% confidence interval, CI, 1.2-2.9; p = 0.0076) independently of age, sex, hypertension and all other risk factors. AAs also had significantly higher odds of having extreme CHS scores ≥3 (OR, 1.3; 95% CI, 1.1-3.6; p = 0.025). Extreme PV was not significantly associated with AA race (OR, 1.3; 95% CI, 0.81-2.1; p = 0.26). Conclusions: AAs from families with early-onset cardiovascular disease are more likely to have extreme DWMVs (a subclinical form of cerebrovascular disease) and an extreme CHS score, but not extreme PV, independently of age and other cardiovascular disease risk factors. These findings suggest that this AA population is at an increased risk for DWMV and may be at an increased risk for future subcortical stroke. Longitudinal studies are required to see if DWMV is predictive of symptomatic subcortical strokes in this population.

OBJECTIVE Coronary atherosclerosis has been associated with systemic arterial remodeling even in nonatherosclerotic vessels. However, it is not known whether systemic remodeling is differentially associated with the cumulative atherosclerotic process, reflected by putatively quiescent calcified plaque (CP), or with active atherosclerosis, consisting of noncalcified plaque (NCP). We thus examined the association of brachial artery diameter (BAD), an artery that does not suffer clinical atherosclerosis, with the presence and the extent of coronary CP and NCP. METHODS We studied 688 apparently healthy, asymptomatic participants from 350 families with a history of early-onset coronary artery disease (

Introduction: Decreased fornix fractional anisotropy (FA) on diffusion tensor imaging (DTI) in normal ageing has been associated with impaired problem solving, working memory and motor tasking, but its role in multi-dimensional cognitive-motor tasks in apparently healthy people has not been studied. Also, the extent of its association with vascular disruption remains unclear. White matter lesions of presumed ischemic origin on MRI are associated with decrements in Grooved Pegboard test (GPBT) in young asymptomatic family members of probands with premature coronary artery disease (CAD). Hypothesis: We hypothesized that decrements in GPBT in this population, is associated with decreased FA in relevant brain regions. Methods: The GPBT was averaged for both hands. DTI was acquired on a Phillips 3T scanner (slice thickness 2.2 mm, field of view 212X212 mm and b-value 700 mm 2 /s). The brain was segmented into 181 regions with Large Deformation Diffeomorphic Metric Mapping using the Eve atlas. Pearson correlations of regional FA values and log-transformed GPBT scores were performed and Multivariable GEE linear regression (adjusted for family relatedness) was done for regions meeting the Bonferroni threshold of 0.00028 (0.05/181). Results: Subjects with DTI and GPBT data were included (N=115, mean age 49± 11 years; mean education 14 ± 3 years; 49% male; 41% African American). GPBT score was normal (106±15) seconds. Higher GPBT (worse performance) was negatively correlated with FA in regions of the left (L) and right (R) frontal and temporal lobes and L&R corpus callosum not meeting Bonferroni threshold (p=0.0046, 0.036, 0.026, 0.0015, 0.02, 0.0007), whereas the L&R fornix and L external capsule (EC) did meet threshold (L fornix R=-0.37, p=5.9E-05; R fornix R=-0.47, p=1.3E-07, L EC R=-0.35, p=8.1E-05). After adjusting for age, sex, race, and education every 25% lower FA in the R fornix was associated with 12% decrement in GBPT (R fornix p=0.05, L fornix and EC p=0.19). Conclusions: Decreased fornix FA is associated with worse manual dexterity in a healthy middle-aged population with a family history of early onset CAD, at risk for future cerebrovascular disease. This suggests injury of the fornix fibers may represent early ischemic injury in this population.

Both genetic and environmental factors contribute to the different biological processes which underlie clinical coronary artery disease (CAD), including atherosclerosis, thrombosis, myocardial infarction, and death. Family history and twin concordance studies consistently demonstrate that CAD is heritable with a significant polygenic component. Elevated cholesterol, blood pressure, and glucose only explain a modest portion of CAD risk and are heritable traits themselves. As a common disease, genetic variants that are highly prevalent in human populations would be expected to contribute to CAD. Since 2007, genome-wide association studies have helped map more than 50 common genetic susceptibility variants for CAD phenotypes. Although some are in genes contributing to the presence of traditional risk factors, most of these variants are in or near novel genes previously not known to be associated with CAD. The challenge remains to determine exactly how genetic variants contribute to CAD so we can better understand the biological mechanisms involved and devise better and more targeted therapeutic and preventive approaches.

Aims Exercise training (ET) has been variably associated with body composition changes among persons with type 2 diabetes (T2DM). The degree to which these changes are related to hyperglycemia remains unclear. Our objective was to investigate the relationship of baseline fasting glucose (FG) to the magnitude of muscle gains and fat loss after ET in individuals with T2DM. Methods Participants were enrolled in the SHAPE-2 trial, a six month supervised aerobic and resistance training intervention (three days/week), at Johns Hopkins. This was a post hoc single arm intervention study of participants who completed the exercise intervention ( n =50). Participants were aged 40–65years and had T2DM that was not treated with insulin. Body composition was assessed by DEXA. Results After 6months of ET, total fat mass decreased (−2.1±3.1kg) and total lean body mass (LBM) increased (0.5±2.0kg) overall, but there was variability among individual participants. There was an increase in % total LBM (1.4±1.9%) and decrease in % total body fat mass (−1.5±2.0%) after ET. Interestingly, each standard deviation (SD) increase in baseline FG (mean=135.5mg/dl; SD=39.0mg/dl) was related to a significant increase in % total LBM (0.54±0.26%, p =0.048) and decrease in % total body fat (−0.57±0.27%, p =0.04) after ET among individual participants. Conclusions Our data demonstrate that muscle gains and fat loss after ET are positively related to baseline hyperglycemia. Further studies are needed to characterize differences in metabolic response following ET among persons with diabetes.

Aims A family history of premature coronary artery disease (CAD) in an apparently healthy individual conveys an increased risk of future CAD. The extent to which inducible myocardial ischaemia exists and is associated with long-term incident CAD in apparently healthy siblings of early-onset CAD patients is unknown. Methods and results Asymptomatic siblings ( n = 1287, aged 30–59 years) of patients with onset of CAD

OBJECTIVE The metabolic syndrome (MetS) is defined as concomitant disorders of lipid and glucose metabolism, central obesity, and high blood pressure, with an increased risk of type 2 diabetes and cardiovascular disease. This study tests whether common genetic variants with pleiotropic effects account for some of the correlated architecture among five metabolic phenotypes that define MetS. RESEARCH DESIGN AND METHODS Seven studies of the STAMPEED consortium, comprising 22,161 participants of European ancestry, underwent genome-wide association analyses of metabolic traits using a panel of ∼2.5 million imputed single nucleotide polymorphisms (SNPs). Phenotypes were defined by the National Cholesterol Education Program (NCEP) criteria for MetS in pairwise combinations. Individuals exceeding the NCEP thresholds for both traits of a pair were considered affected. RESULTS Twenty-nine common variants were associated with MetS or a pair of traits. Variants in the genes LPL, CETP, APOA5 (and its cluster), GCKR (and its cluster), LIPC, TRIB1, LOC100128354/MTNR1B, ABCB11, and LOC100129150 were further tested for their association with individual qualitative and quantitative traits. None of the 16 top SNPs (one per gene) associated simultaneously with more than two individual traits. Of them 11 variants showed nominal associations with MetS per se. The effects of 16 top SNPs on the quantitative traits were relatively small, together explaining from ∼9% of the variance in triglycerides, 5.8% of high-density lipoprotein cholesterol, 3.6% of fasting glucose, and 1.4% of systolic blood pressure. CONCLUSIONS Qualitative and quantitative pleiotropic tests on pairs of traits indicate that a small portion of the covariation in these traits can be explained by the reported common genetic variants.

A 58 kb region on chromosome 9p21.3 has consistently shown strong association with coronary artery disease (CAD) in multiple genome-wide association studies in populations of European and East Asian ancestry. In this study, we sought to further characterize the role of genetic variants in 9p21.3 in African American individuals. Apparently healthy African American siblings (n = 548) of patients with documented CAD60 years of age were genotyped and followed for incident CAD for up to 17 years. Tests of association for 86 single-nucleotide polymorphisms (SNPs) across the 9p21.3 region in a generalized estimating equation logistic framework under an additive model adjusting for traditional risk factors, family, follow-up time and population stratification were performed. A single SNP within the CDKN2B gene met stringent criteria for statistical significance, including permutation-based evaluations. This variant, rs3217989, was common (minor allele (G) frequency 0.242), conveyed protection against CAD (odds ratio (OR) = 0.19, 95% confidence interval (CI): 0.07 to 0.50, P = 0.0008) and was replicated in a combined analysis of two additional case/control studies of prevalent CAD/MI in African Americans (n = 990, P = 0.024, OR = 0.779, 95% CI: 0.626-0.968). This is the first report of a CAD association signal in a population of African ancestry with a common variant within the CDKN2B gene, independent from previous findings in European and East Asian ancestry populations. The findings demonstrate a significant protective effect against incident CAD in African American siblings of persons with premature CAD, with replication in a combination of two additional African American cohorts.

Markers of systemic inflammation, including blood leukocyte count, are associated with increased cardiovascular risk, but the mechanisms underlying this association are unclear. Leukocytes may promote platelet reactivity and thrombus formation, providing a basis for increased risk, but a relation between leukocyte count and platelet function has not been studied.We evaluated the relation of blood leukocyte count, C-reactive protein (CRP), and interleukin-6 (IL-6) to platelet aggregation to collagen, ADP and arachidonic acid, and to urinary excretion of 11-dehydro thromboxane B2. Studies were conducted in 1600 individuals (45.0+/-12.9 years, 42.7% male) at risk for coronary artery disease (CAD) before and after low dose aspirin.At baseline, platelet reactivity increased with increasing quartile of leukocyte count (median counts for each quartile were normal) for all measures of platelet function (P0.0001). These relations were unchanged by aspirin. The relation between leukocyte count and each measure of platelet reactivity remained significant (P0.05) after multivariable adjustment for CRP, IL-6, cardiac risk factors, hematologic variables, and platelet thromboxane production. CRP and IL-6 were independently associated with few measures of platelet reactivity.Increasing quartile of leukocyte count, even within the normal range, is associated with increasing platelet reactivity in individuals at risk for CAD. This relationship is not altered by aspirin and is independent of inflammatory markers and platelet thromboxane production. Additional studies are needed to determine the mechanism(s) for this association and therapies to reduce cardiovascular risk in patients with elevated leukocyte counts.

Antiplatelet drugs are well-established therapies for acute coronary syndromes and for the primary and secondary prevention of coronary artery disease, stroke, and peripheral vascular disease. However, wide interindividual variability exists in the degree of platelet suppression among patients treated with antiplatelet drugs, and many individuals develop atherothrombotic events while on therapy. Although many potential mechanisms may contribute to the response variation observed, there is accumulating evidence that polymorphisms of genes from multiple biologic pathways involved in platelet activation are at least partly responsible for variable platelet responsiveness and potentially responsible for clinical failure of antiplatelet therapy.

Measurement of the inflammatory biomarker high sensitivity C-reaction protein (hsCRP) has been proposed for assessment of risk for cardiovascular disease (CVD). It remains unclear which patient populations would benefit from and should be targeted for hsCRP testing. Current data indicate that hsCRP levels are independently associated with risk of CVD, including both coronary events and stroke, in various asymptomatic populations; add predictive power to current coronary risk scores for some intermediate risk individuals; and are associated with clinical outcomes in high risk individuals treated with statin therapy. HsCRP levels are also associated with incident diabetes and CVD outcomes in patients with the metabolic syndrome. There is a growing body of evidence to support recommendations for measurement of hsCRP in selected asymptomatic individuals deemed to be at intermediate risk of CVD according to traditional risk factor assessment and who do not already warrant treatment with chronic aspirin and statin therapy, and selected secondary CVD prevention patients for further risk stratification in combination with LDL cholesterol.

Recent clinical trials in patients with coronary artery disease (CAD) provide evidence that low-density lipoprotein cholesterol (LDL-C) levels should be lowered even further to prevent recurrent CAD. However, despite more aggressive interventions for lowering LDL-C levels, the majority of CAD events go undeterred, perhaps related to the fact that intervention was not started earlier in life or that LDL-C levels represent an incomplete picture of atherogenic potential. Nevertheless, LDL-C remains the contemporary standard as the primary goal for aggressive LDL reduction. If triglycerides are >200 mg/dl, the measurement of non-high-density lipoprotein cholesterol (HDL-C) is recommended. Measurement of apolipoprotein (apo)B has been shown in nearly all studies to outperform LDL-C and non-HDL-C as a predictor of CAD events and as an index of residual CAD risk. This is because apoB reflects the total number of atherogenic apoB-containing lipoproteins and is a superior predictor of the number of low-density lipoprotein particles (LDL-P). Estimates of LDL-P and size can also be made by nuclear magnetic resonance spectroscopy, density gradient ultracentrifugation, and gradient gel electrophoresis. Although a number of studies show that such estimates predict CAD, LDL-P, and size often accompany low HDL-C and high triglyceride levels, and therefore such additional lipoprotein testing has not been recommended for routine screening and follow-up. Because apoB is a superior predictor of LDL-P, we recommend that apoB and the apoB/apoA-I ratio be determined after measurement of LDL-C, non-HDL-C, and the ratio of total cholesterol/HDL-C to better predict CAD and assess efficacy of treatment.

In families, well-known monogenic high-density lipoprotein cholesterol (HDL-C) disorders characterized by extreme HDL-C levels on both ends of the continuum occur in multiple HDL pathways and can confer increased risk for atherosclerotic disease. Polygenic HDL-C variants have been more difficult to identify. In many family and twin studies in different populations, HDL-C levels have been shown to be highly heritable, explaining, on average, between 40% and 60% of between-individual variation. This review of abnormal HDL in families addresses known monogenic HDL disorders and HDL-C heritability in the general population, and presents novel data on the heritability of HDL-C in families with a history of premature coronary artery disease. We conclude that levels of HDL-C and HDL abnormalities are largely under genetic control and environmental and behavioral factors alone have only a modest impact. While rare, monogenic disorders offer considerable insight into the genetics of HDL regulation. Moderate to high heritability estimates across different family populations suggest that future genetic studies will be successful in identifying HDL genetic trait loci and that translational studies will ultimately lead to therapies that optimize the cardiovascular protective benefits of HDL.

Introduction: Basic research shows that adipose tissue is proinflammatory, and inflammation in turn may cause adipose tissue accumulation through insulin resistance. However, it is not well understood whether adiposity or inflammation, or equally both, are drivers of this vicious cycle. We examined this question through longitudinal structural equation modeling (SEM). Methods: We analyzed data from 869 GeneSTAR Study participants from 374 families who were free of clinical cardiovascular disease throughout the follow-up period, and had two study visits 2 to 8 years apart. Body Mass Index (BMI) was used as a measure of adiposity, and log transformed high sensitivity C-Reactive Protein (CRP) as a measure of inflammatory state. The crossed lag SEM for correlations is presented in the Figure, adjusting for demographic factors and smoking during the two visits. The predictive associations of follow-up BMI and CRP with baseline CRP and BMI, respectively, are adjusted for cross sectional correlations and longitudinal inertia of variables. We also estimated the beta coefficients of the crossed lag associations using generalized SEM, accounting for non-independence of families. Results: Baseline BMI was associated with follow-up CRP (3.6% increase/BMI unit, p Conclusions: Higher adiposity is the driver of its vicious cycle with inflammation. For future studies, we conjecture that weight control is likely to be more effective as compared to treatment of inflammation in improving the coupled metabolic and inflammatory profile over time.