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Background : Metabolic syndrome (MetS) is characterized by a cluster of biological irregularities. The purpose of this analysis was to examine the association of MetS with BC among Nigerian women, and for the first time evaluate this association by molecular subtype. Methods : MetS was defined as having at least 3 out of 5 of: high blood pressure (≥130/85 mm Hg), reduced HDL ( 150 mg/dL), high waist circumference (≥80 cm), and prior diagnosis of diabetes or elevated fasting glucose level (≥100 mg/dL). Among 296 newly diagnosed BC cases and 259 healthy controls, multivariable logistic regression models were utilized to estimate adjusted odds ratios (aOR) and 95% confidence intervals (95% CI) for the association between MetS and BC overall. Multinomial logistic regression models were used to evaluate each molecular subtype (Luminal A, Luminal B, HER2-enriched and triple-negative or TNBC). Results : After adjusting for age, socio-demographic and reproductive risk factors, there was a positive association between MetS and BC (aOR: 1.84, 95% CI: 1.07, 3.16). In stratified analyses, MetS was associated with BC regardless of BMI status; however, the estimate was significant only among normal weight women (aOR: 3.85; 95% CI: 1.25, 11.90). MetS was significantly associated with TNBC subtype (aOR: 4.37, 95% CI: 1.67, 11.44); associations for other molecular subtypes were not statistically significant. Conclusion : MetS appears to be a robust risk factor for BC, particularly for TNBC. Public health and clinical interventions can provide substantial benefits in reducing the burden of MetS and preventing BC among Nigerian women. MICRO-ABSTRACT : Metabolic syndrome is a cluster of biological irregularities that is a known risk factor for cardiovascular disease, stroke, and diabetes. In a case-control study of 555 Nigerian women, we observed that metabolic syndrome was strongly associated with breast cancer and the aggressive triple-negative molecular subtype, highlighting a need for clinical and lifestyle interventions targeting metabolic syndrome to reduce breast cancer risk in this population.

BACKGROUND: Epigenome-wide association studies identified the cg00574958 DNA methylation site at the carnitine palmitoyltransferase-1A (CPT1A) gene to be associated with reduced risk of metabolic diseases (hypertriglyceridemia, obesity, type 2 diabetes, hypertension, metabolic syndrome), but the mechanism underlying these associations is unknown. OBJECTIVES: We aimed to elucidate whether carbohydrate and fat intakes modulate cg00574958 methylation and the risk of metabolic diseases. METHODS: We examined associations between carbohydrate (CHO) and fat (FAT) intake, as percentages of total diet energy, and the CHO/FAT ratio with CPT1A-cg00574958, and the risk of metabolic diseases in 3 populations (Genetics of Lipid Lowering Drugs and Diet Network, n = 978; Framingham Heart Study, n = 2331; and REgistre GIroní del COR study, n = 645) while adjusting for confounding factors. To understand possible causal effects of dietary intake on the risk of metabolic diseases, we performed meta-analysis, CPT1A transcription analysis, and mediation analysis with CHO and FAT intakes as exposures and cg00574958 methylation as the mediator. RESULTS: We confirmed strong associations of cg00574958 methylation with metabolic phenotypes (BMI, triglyceride, glucose) and diseases in all 3 populations. Our results showed that CHO intake and CHO/FAT ratio were positively associated with cg00574958 methylation, whereas FAT intake was negatively correlated with cg00574958 methylation. Meta-analysis further confirmed this strong correlation, with β = 58.4 ± 7.27, P = 8.98 x 10(-16) for CHO intake; β = −36.4 ± 5.95, P = 9.96 x 10(-10) for FAT intake; and β = 3.30 ± 0.49, P = 1.48 x 10(-11) for the CHO/FAT ratio. Furthermore, CPT1A mRNA expression was negatively associated with CHO intake, and positively associated with FAT intake, and metabolic phenotypes. Mediation analysis supports the hypothesis that CHO intake induces CPT1A methylation, hence reducing the risk of metabolic diseases, whereas FAT intake inhibits CPT1A methylation, thereby increasing the risk of metabolic diseases. CONCLUSIONS: Our results suggest that the proportion of total energy supplied by CHO and FAT can have a causal effect on the risk of metabolic diseases via the epigenetic status of CPT1A. Study registration at https://www.clinicaltrials.gov/: the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN)—NCT01023750; and the Framingham Heart Study (FHS)—NCT00005121.

BACKGROUND: Asthma is a common respiratory disorder with a highly heterogeneous nature that remains poorly understood. The objective was to use whole genome sequencing (WGS) data to identify regions of common genetic variation contributing to lung function in individuals with a diagnosis of asthma. METHODS: WGS data were generated for 1,053 individuals from trios and extended pedigrees participating in the family-based Genetic Epidemiology of Asthma in Costa Rica study. Asthma affection status was defined through a physician’s diagnosis of asthma, and most participants with asthma also had airway hyperresponsiveness (AHR) to methacholine. Family-based association tests for single variants were performed to assess the associations with lung function phenotypes. RESULTS: A genome-wide significant association was identified between baseline FEV(1)/FVC ratio and a single-nucleotide polymorphism in the top hit cysteine-rich secretory protein LCCL domain-containing 2 (CRISPLD2) (rs12051168; P = 3.6 × 10(−8) in the unadjusted model) that retained suggestive significance in the covariate-adjusted model (P = 5.6 × 10(−6)). Rs12051168 was also nominally associated with other related phenotypes: baseline FEV(1) (P = 3.3 × 10(−3)), postbronchodilator (PB) FEV(1) (7.3 × 10(−3)), and PB FEV(1)/FVC ratio (P = 2.7 × 10(−3)). The identified baseline FEV(1)/FVC ratio and rs12051168 association was meta-analyzed and replicated in three independent cohorts in which most participants with asthma also had confirmed AHR (combined weighted z-score P = .015) but not in cohorts without information about AHR. CONCLUSIONS: These findings suggest that using specific asthma characteristics, such as AHR, can help identify more genetically homogeneous asthma subgroups with genotype-phenotype associations that may not be observed in all children with asthma. CRISPLD2 also may be important for baseline lung function in individuals with asthma who also may have AHR.

BACKGROUND: The putative functional variant −265T>C (rs5082) within the APOA2 promoter has shown consistent interactions with saturated fatty acid (SFA) intake to influence the risk of obesity. OBJECTIVE: The aim of this study was to implement an integrative approach to characterize the molecular basis of this interaction. DESIGN: We conducted an epigenome-wide scan on 80 participants carrying either the rs5082 CC or TT genotypes and consuming either a low-SFA (C genotype, promoting an APOA2 expression difference between APOA2 genotypes on a high-SFA diet, and modulating BCAA and tryptophan metabolic pathways. These findings identify potential mechanisms by which this highly reproducible gene-diet interaction influences obesity risk, and contribute new insights to ongoing investigations of the relation between SFA and human health. This study was registered at clinicaltrials.gov as NCT03452787.

Background Stroke risk can be quantified using risk factors whose effect sizes vary by geography and race. No stroke risk assessment tool exists to estimate aggregate stroke risk for indigenous African. Objectives To develop Afrocentric risk-scoring models for stroke occurrence. Materials and Methods We evaluated 3533 radiologically confirmed West African stroke cases paired 1:1 with age-, and sex-matched stroke-free controls in the SIREN study. The 7,066 subjects were randomly split into a training and testing set at the ratio of 85:15. Conditional logistic regression models were constructed by including 17 putative factors linked to stroke occurrence using the training set. Significant risk factors were assigned constant and standardized statistical weights based on regression coefficients (β) to develop an additive risk scoring system on a scale of 0–100%. Using the testing set, Receiver Operating Characteristics (ROC) curves were constructed to obtain a total score to serve as cut-off to discriminate between cases and controls. We calculated sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) at this cut-off. Results For stroke occurrence, we identified 15 traditional vascular factors. Cohen's kappa for validity was maximal at a total risk score of 56% using both statistical weighting approaches to risk quantification and in both datasets. The risk score had a predictive accuracy of 76% (95%CI: 74–79%), sensitivity of 80.3%, specificity of 63.0%, PPV of 68.5% and NPV of 76.2% in the test dataset. For ischemic strokes, 12 risk factors had predictive accuracy of 78% (95%CI: 74–81%). For hemorrhagic strokes, 7 factors had a predictive accuracy of 79% (95%CI: 73–84%). Conclusions The SIREN models quantify aggregate stroke risk in indigenous West Africans with good accuracy. Prospective studies are needed to validate this instrument for stroke prevention.

BACKGROUND: The burden of stroke in Africa is high. Understanding how age associates with major modifiable stroke risk factors could inform tailored demographic stroke prevention strategies. PURPOSE: To quantify the magnitude and direction of the effect sizes of key modifiable stroke risk factors according to three age groups: 65 years (elderly) in West Africa. METHODS: This was a case-control study involving 15 sites in Ghana and Nigeria. Cases included adults aged ≥18 years with CT/MRI scan-typed stroke. Controls were age-and gender-matched stroke-free adults. Detailed evaluations for vascular, lifestyle and psychosocial factors were performed. We estimated adjusted odds ratios (aOR) using conditional logistic regression and population attributable risk (PAR) with 95% Confidence Interval of vascular risk factors by age groups. RESULTS: Among 3553 stroke cases, 813 (22.9%) were young, 1441 (40.6%) were middle-aged and 1299 (36.6%) were elderly. Among the 5 co-shared risk factors, dyslipidemia with PAR and aOR (95%CI) of 62.20% (52.82–71.58) and 4.13 (2.64–6.46) was highest among the young age group; hypertension with PAR of 94.31% (91.82–96.80) and aOR of 28.93 (15.10–55.44) was highest among the middle-age group. Diabetes with PAR of 32.29% (27.52–37.05) and aOR of 3.49 (2.56–4.75); meat consumption with PAR of 42.34%(32.33–52.35) and aOR of 2.40 (1.76, 3.26); and non-consumption of green vegetables, PAR of 16.81%(12.02–21.60) and aOR of 2.23 (1.60–3.12) were highest among the elderly age group. However confidence intervals of risk estimates over-lapped across age groups. Additionally, among the young age group cigarette smoking, psychosocial stress and cardiac disease were independently associated with stroke. Furthermore, education, stress, physical inactivity and salt intake were associated with stroke in the middle-age group while cardiac disease was associated with stroke in the elderly age group. CONCLUSION: There is a differential influence of age on the associations of major risk factors with stroke in this West African cohort. Targeting modifiable factors predominant within an age group may be more effective as a stroke prevention strategy.

Background The optimal level of sodium intake remains controversial. Objectives This study sought to determine whether examination of left ventricular longitudinal strain (LS), circumferential strain, and e′ velocity can provide insight into thresholds for the detrimental effects of estimated sodium intake (ESI) on subclinical cardiovascular disease. Methods We performed speckle-tracking analysis on HyperGEN (Hypertension Genetic Epidemiology Network) study echocardiograms with available urinary sodium data (N = 2,996). We evaluated the associations among ESI and LS, circumferential strain, and e′ velocity using multivariable-adjusted linear mixed-effects models (to account for relatedness among subjects) with linear splines (spline 1: ESI ≤3.7 g/day, spline 2: ESI >3.7 g/day based on visual inspection of fractional polynomial plots of the association between ESI and indices of strain and e′ velocity). We performed mediation analysis to understand the indirect effects of systolic blood pressure and serum aldosterone on the relationship between ESI and strain and e′ velocity. Results Mean age of participants was 49 ± 14 years, 57% were female, 50% were African American, and 54% had hypertension. The median ESI was 3.73 (interquartile range: 3.24, 4.25) g/day. ESI >3.7 g/day was associated with larger left atrial and left ventricular dimensions (p 3.7 g/day was associated with both strain parameters and e′ velocity (p 0.05 for all comparisons). There were significant interactions by potassium excretion for circumferential strain. Mediation analysis suggested that systolic blood pressure explained 14% and 20% of the indirect effects between ESI and LS and e′ velocity, respectively, whereas serum aldosterone explained 19% of the indirect effects between ESI and LS. Conclusions ESI >3.7 g/day is associated with adverse cardiac remodeling and worse systolic strain and diastolic e′ velocity.

BACKGROUND: Trimethylamine-N-oxide (TMAO), an atherogenic metabolite species, has emerged as a possible new risk factor for cardiovascular disease. Animal studies have shown that circulating TMAO levels are regulated by genetic and environmental factors. However, large-scale human studies have failed to replicate the observed genetic associations, and epigenetic factors such as DNA methylation have never been examined in relation to TMAO levels. METHODS AND RESULTS: We used data from the family-based Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) to investigate the heritable determinants of plasma TMAO in humans. TMAO was not associated with other plasma markers of cardiovascular disease, e.g. lipids or inflammatory cytokines. We first estimated TMAO heritability at 27%, indicating a moderate genetic influence. We used 1000 Genomes imputed data (n=626) to estimate genome-wide associations with TMAO levels, adjusting for age, sex, family relationships, and study site. The genome-wide study yielded one significant hit at the genome-wide level, located in an intergenic region on chromosome 4. We subsequently quantified epigenome-wide DNA methylation using the Illumina Infinium array on CD4+ T-cells. We tested for association of methylation loci with circulating TMAO (n=847), adjusting for age, sex, family relationships, and study site as the genome-wide study plus principal components capturing CD4+ T-cell purity. Upon adjusting for multiple testing, none of the epigenetic findings were statistically significant. CONCLUSIONS: Our findings contribute to the growing body of evidence suggesting that neither genetic nor epigenetic factors play a critical role in establishing circulating TMAO levels in humans. This work was funded by the American Heart Association (14CRP18060003, PI: Aslibekyan) and the National Institutes of Health (R01HL104135, PI: Arnett). Sí

While a recent meta-analysis of prospective studies reported that coffee consumption is associated with a lower risk of cardiovascular disease mortality, limited and inconsistent data are available on the relation of coffee intake with subclinical disease. Thus, the aim of the present study was to see the association of coffee consumption with the prevalence of atherosclerotic plaque in the coronary arteries in NHLBI Family Heart Study.In a cross-sectional design, we studied 1929 participants of the NHLBI Family Heart Study without known coronary heart disease. Coffee consumption was assessed by a semi-quantitative food frequency questionnaire and coronary-artery calcium (CAC) was measured by cardiac computed tomography. We defined prevalent CAC as an Agatston score of ≥100 and used generalized estimating equations to calculate prevalence ratios of CAC as well as a sensitivity analysis at a range of cutpoints for CAC.Mean age was 56.7 years and 59% of the study subjects were female. In adjusted analysis for age, sex, BMI, smoking, alcohol, physical activity, field center, and energy intake, prevalence ratio (95% CI) for CAC was 1.0 (reference), 0.92 (0.57-1.49), 1.34 (0.86-2.08), 1.30 (0.84-2.02), and 0.99 (0.60-1.64) for coffee consumption of almost never,1/day, 1/day, 2-3/day, and ≥4 cups/day, respectively. In a sensitivity analysis, there was no evidence of association between coffee consumption and prevalent CAC when CAC cut points of 0, 50, 150, 200, and 300 were used.These data do not provide evidence for an association between coffee consumption and prevalent CAC in adult men and women.

Cluster of differentiation 36 (CD36) variants influence fasting lipids and risk of metabolic syndrome, but their impact on postprandial lipids, an independent risk factor for cardiovascular disease, is unclear. We determined the effects of SNPs within a ~410 kb region encompassing CD36 and its proximal and distal promoters on chylomicron (CM) remnants and LDL particles at fasting and at 3.5 and 6 h following a high-fat meal (Genetics of Lipid Lowering Drugs and Diet Network study, n = 1,117). Five promoter variants associated with CMs, four with delayed TG clearance and five with LDL particle number. To assess mechanisms underlying the associations, we queried expression quantitative trait loci, DNA methylation, and ChIP-seq datasets for adipose and heart tissues that function in postprandial lipid clearance. Several SNPs that associated with higher serum lipids correlated with lower adipose and heart CD36 mRNA and aligned to active motifs for PPARγ, a major CD36 regulator. The SNPs also associated with DNA methylation sites that related to reduced CD36 mRNA and higher serum lipids, but mixed-model analyses indicated that the SNPs and methylation independently influence CD36 mRNA. The findings support contributions of CD36 SNPs that reduce adipose and heart CD36 RNA expression to inter-individual variability of postprandial lipid metabolism and document changes in CD36 DNA methylation that influence both CD36 expression and lipids.

BackgroundGenetic factors that influence kidney traits have been understudied for low frequency and ancestry-specific variants.MethodsWe combined whole genome sequencing (WGS) data from 23,732 participants from 10 NHLBI Trans-Omics for Precision Medicine (TOPMed) Program multi-ethnic studies to identify novel loci for estimated glomerular filtration rate (eGFR). Participants included European, African, East Asian, and Hispanic ancestries. We applied linear mixed models using a genetic relationship matrix estimated from the WGS data and adjusted for age, sex, study, and ethnicity.FindingsWhen testing single variants, we identified three novel loci driven by low frequency variants more commonly observed in non-European ancestry (PRKAA2, rs180996919, minor allele frequency [MAF] 0.04%, P=6.1×10-11; METTL8, rs116951054, MAF 0.09%, P=4.5×10-9; and MATK, rs539182790, MAF 0.05%, P=3.4×10-9). We also replicated two known loci for common variants (rs2461702, MAF=0.49, P=1.2×10-9, nearest gene GATM, and rs71147340, MAF=0.34, P=3.3×10-9, CDK12). Testing aggregated variants within a gene identified the MAF gene. A statistical approach based on local ancestry helped to identify replication samples for ancestry-specific variants.InterpretationThis study highlights challenges in studying variants influencing kidney traits that are low frequency in populations and more common in non-European ancestry.

BACKGROUND: Previous studies have suggested that for clinical purposes, subjects with fasting triglycerides (TGs) between 89–180 mg/dl (1–2 mmol/l) would benefit from postprandial TGs testing. OBJECTIVE: To determine the postprandial TG response in 2 independent studies and validate who should benefit diagnostically from an oral-fat tolerance test (OFTT) in clinical practice. METHODS: A population of 1002 patients with coronary heart disease (CHD) from the CORDIOPREV clinical trial and 1115 white US subjects from the GOLDN study underwent OFTTs. Subjects were classified into 3 groups according to fasting cut points of TGs to predict the usefulness of OFTT: (1) TG < 89 mg/dl ( 180 mg/dl (>2 mmol/l). Postprandial TG concentration at any point > 220 mg/dl (>2.5 mmol/l) has been pre-established as an undesirable postprandial response. RESULTS: Of the total, 49% patients with CHD and 42% from the general population showed an undesirable response after the OFTT. The prevalence of undesirable postprandial TG in the CORDIOPREV clinical trial was 12.8, 50.3, and 89.7%, in group 1, 2, and 3, respectively (P < .001) and 11.2, 58.1, and 97.5% in group 1, 2, and 3, respectively (P < .001) in the GOLDN study. CONCLUSIONS: These two studies validate the predictive values reported in a previous consensus. Moreover, the findings of the CORDIOPREV and GOLDN studies show that an OFTT is useful to identify postprandial hyperlipidemia in subjects with fasting TG between 1–2 mmol/l (89–180 mg/dL), because approximately half of them have hidden postprandial hyperlipidemia, which may influence treatment. An OFTT does not provide additional information regarding postprandial hyperlipidemia in subjects with low TG (2 mmol/l, >180 mg/dl).

Background: Data are limited on the relation between dietary patterns and left ventricular (LV) structure and function. Objective: We examined cross-sectional associations of a diet-score assessment of a Mediterranean dietary pattern with LV mass, volume, mass-to-volume ratio, stroke volume, and ejection fraction. Design: We measured LV variables with the use of cardiac MRI in 4497 participants in the Multi-Ethnic Study of Atherosclerosis study who were aged 45–84 y and without clinical cardiovascular disease. We calculated a Mediterranean diet score from intakes of fruit, vegetables, nuts, legumes, whole grains, fish, red meat, the monounsaturated fat:saturated fat ratio, and alcohol that were self-reported with the use of a food-frequency questionnaire. We used linear regression with adjustment for body size, physical activity, and cardiovascular disease risk factors to model associations and assess the shape of these associations (linear or quadratic). Results: The Mediterranean diet score had a slight U-shaped association with LV mass (adjusted means: 146, 145, 146, and 147 g across quartiles of diet score, respectively; P-quadratic trend = 0.04). The score was linearly associated with LV volume, stroke volume, and ejection fraction: for each +1-U difference in score, LV volume was 0.4 mL higher (95% CI: 0.0, 0.8 mL higher), the stroke volume was 0.5 mL higher (95% CI: 0.2, 0.8 mL higher), and the ejection fraction was 0.2 percentage points higher (95% CI: 0.1, 0.3 percentage points higher). The score was not associated with the mass-to-volume ratio. Conclusions: A higher Mediterranean diet score is cross-sectionally associated with a higher LV mass, which is balanced by a higher LV volume as well as a higher ejection fraction and stroke volume. Participants in this healthy, multiethnic sample whose dietary patterns most closely conformed to a Mediterranean-type pattern had a modestly better LV structure and function than did participants with less–Mediterranean-like dietary patterns. This trial was registered at clinicaltrials.gov as {"type":"clinical-trial","attrs":{"text":"NCT00005487","term_id":"NCT00005487"}}NCT00005487.

BACKGROUND S100 calcium-binding protein A9 (S100A9) has previously been identified as a type 2 diabetes (T2D) gene. However, this finding requires independent validation and more in-depth analyses in other populations and ancestries. OBJECTIVES We aimed to replicate the associations between an S100A9 variant and insulin resistance and T2D and to initiate an investigation of potential interactions with the habitual diet in several independent populations. DESIGN We investigated the association of the S100A9 variant rs3014866 with insulin resistance and T2D risk and its interactions with diet in 3 diverse populations as follows: the CORDIOPREV (Coronary Diet Intervention with Olive Oil and Cardiovascular Prevention; n = 711), which consisted of Spanish white adults; the GOLDN (Genetics of Lipids Lowering Drugs and Diet Network; n = 818), which involved North American non-Hispanic white adults; and Hispanic adults who participated in the BPRHS (Boston Puerto Rican Health Study; n = 1155). RESULTS Meta-analysis indicated that T carriers presented a lower risk of T2D than CC carriers (pooled OR: 0.714; 95% CI: 0.584, 0.845; P = 0.002). In all 3 populations (CORDIOPREV, GOLDN, and BPRHS), we showed a significant interaction between the rs3014866 single nucleotide polymorphism and dietary SFA:carbohydrate ratio intake for the homeostasis model assessment of insulin resistance (HOMA-IR) (P = 0.028, P = 0.017, and P = 0.026, respectively). CC carriers had a significantly higher HOMA-IR only when SFA:carbohydrate intake was high (P = 0.045 for the CORDIOPREV, P = 0.033 for the GOLDN, and P = 0.046 for the BPRHS) but not when SFA:carbohydrate ratio intake was low. CONCLUSIONS The minor allele (T) of the S100A9 variant rs3014866 is associated with lower T2D risk in 3 populations of different ancestries. Note that individuals with the high-risk CC genotype may be more likely to benefit from a low SFA:carbohydrate ratio intake to improve insulin resistance as evaluated with the use of the HOMA-IR. These trials were registered at clinicaltrials.gov as NCT00924937 (CORDIOPREV), NCT00083369 (GOLDN), and NCT01231958 (BPRHS).

The understanding of the genetic basis of neurological disorders has grown rapidly in the last two decades. Despite the genomic heterogeneity within African populations, large-scale candidate gene or linkage and exome studies are lacking. However, current knowledge on neurogenetics in African populations is limited and geographically very uneven. Isolated reports indicate the existence of autosomal dominant or recessive conditions incorporating cerebrovascular, movement, neuromuscular, seizure and motor neuron disorders in Africans. In addition, few African families with neurodegenerative disorders associated with dementia have been characterized in North, West and South Africa. The current insurgency in genomic research triggered by among others the Human Health and Heredity (H3) Africa Initiative indicates that there are unique opportunities to advance our knowledge and understanding of the influence of genomic variation on the pattern, presentations and prognosis of neurological disorders in Africa. These have enormous potential to unmask novel genes and molecular pathways germane to the neurobiology of brain disorders. It would facilitate the development of novel diagnostics, preventative and targeted treatments in the new paradigm of precision medicine. Nevertheless, it is crucial to strike a balance between effective traditional public health strategies and personalized genome based care. The translational barriers can be overcome through robust stakeholder engagement and sustainable multilevel, multigenerational and multidisciplinary capacity building and infrastructural development for genomic medicine in Africa.

The triglyceride (TG) response to a high-fat meal (postprandial lipemia, PPL) affects cardiovascular disease risk and is influenced by genes and environment. Genes involved in lipid metabolism have dominated genetic studies of PPL TG response. We sought to elucidate common genetic variants through a genome-wide association (GWA) study in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN).The GOLDN GWAS discovery sample consisted of 872 participants within families of European ancestry. Genotypes for 2,543,887 variants were measured or imputed from HapMap. Replication of our top results was performed in the Heredity and Phenotype Intervention (HAPI) Heart Study (n = 843). PPL TG response phenotypes were constructed from plasma TG measured at baseline (fasting, 0 hour), 3.5 and 6 hours after a high-fat meal, using a random coefficient regression model. Association analyses were adjusted for covariates and principal components, as necessary, in a linear mixed model using the kinship matrix; additional models further adjusted for fasting TG were also performed. Meta-analysis of the discovery and replication studies (n = 1715) was performed on the top SNPs from GOLDN.GOLDN revealed 111 suggestive (p1E-05) associations, with two SNPs meeting GWA significance level (p5E-08). Of the two significant SNPs, rs964184 demonstrated evidence of replication (p = 1.20E-03) in the HAPI Heart Study and in a joint analysis, was GWA significant (p = 1.26E-09). Rs964184 has been associated with fasting lipids (TG and HDL) and is near ZPR1 (formerly ZNF259), close to the APOA1/C3/A4/A5 cluster. This association was attenuated upon additional adjustment for fasting TG.This is the first report of a genome-wide significant association with replication for a novel phenotype, namely PPL TG response. Future investigation into response phenotypes is warranted using pathway analyses, or newer genetic technologies such as metabolomics.

Circulating trans fatty acids (TFAs), which cannot be synthesized by humans, are linked to adverse health outcomes. Although TFAs are obtained from diet, little is known about subsequent influences (e.g., relating to incorporation, metabolism, or intercompetition with other fatty acids) that could alter circulating concentrations and possibly modulate or mediate impacts on health.The objective was to elucidate novel biologic pathways that may influence circulating TFAs by evaluating associations between common genetic variation and TFA biomarkers.We performed meta-analyses using 7 cohorts of European-ancestry participants (n = 8013) having measured genome-wide variation in single-nucleotide polymorphisms (SNPs) and circulating TFA biomarkers (erythrocyte or plasma phospholipids), including trans-16:1n-7, total trans-18:1, trans/cis-18:2, cis/trans-18:2, and trans/trans-18:2. We further evaluated SNPs with genome-wide significant associations among African Americans (n = 1082), Chinese Americans (n = 669), and Hispanic Americans (n = 657) from 2 of these cohorts.Among European-ancestry participants, 31 SNPs in or near the fatty acid desaturase (FADS) 1 and 2 cluster were associated with cis/trans-18:2; a top hit was rs174548 (β = 0.0035, P = 4.90 × 10(-15)), an SNP previously associated with circulating n-3 and n-6 polyunsaturated fatty acid concentrations. No significant association was identified for other TFAs. rs174548 in FADS1/2 was also associated with cis/trans-18:2 in Hispanic Americans (β = 0.0053, P = 1.05 × 10(-6)) and Chinese Americans (β = 0.0028, P = 0.002) but not African Americans (β = 0.0009, P = 0.34); however, in African Americans, fine mapping identified a top hit in FADS2 associated with cis/trans-18:2 (rs174579: β = 0.0118, P = 4.05 × 10(-5)). The association between rs174548 and cis/trans-18:2 remained significant after further adjustment for individual circulating n-3 and n-6 fatty acids, except arachidonic acid. After adjustment for arachidonic acid concentrations, the association between rs174548 and cis/trans-18:2 was nearly eliminated in European-ancestry participants (β-coefficient reduced by 86%), with similar reductions in Hispanic Americans and Chinese Americans.Our findings provide novel evidence for genetic regulation of cis/trans-18:2 by the FADS1/2 cluster and suggest that this regulation may be influenced/mediated by concentrations of arachidonic acid, an n-6 polyunsaturated fat.

Very long-chain saturated fatty acids (VLSFAs) are saturated fatty acids with 20 or more carbons. In contrast to the more abundant saturated fatty acids, such as palmitic acid, there is growing evidence that circulating VLSFAs may have beneficial biological properties. Whether genetic factors influence circulating levels of VLSFAs is not known. We investigated the association of common genetic variation with plasma phospholipid/erythrocyte levels of three VLSFAs by performing genome-wide association studies in seven population-based cohorts comprising 10,129 subjects of European ancestry. We observed associations of circulating VLSFA concentrations with common variants in two genes, serine palmitoyl-transferase long-chain base subunit 3 (SPTLC3), a gene involved in the rate-limiting step of de novo sphingolipid synthesis, and ceramide synthase 4 (CERS4). The SPTLC3 variant at rs680379 was associated with higher arachidic acid (20:0 , P = 5.81 × 10(-13)). The CERS4 variant at rs2100944 was associated with higher levels of 20:0 (P = 2.65 × 10(-40)) and in analyses that adjusted for 20:0, with lower levels of behenic acid (P = 4.22 × 10(-26)) and lignoceric acid (P = 3.20 × 10(-21)). These novel associations suggest an inter-relationship of circulating VLSFAs and sphingolipid synthesis.

Cardiovascular disease, the leading cause of death in the United States and worldwide, accounts for substantial suffering and healthcare-related expenditures.1–3 For more than 30 years, the American Heart Association (AHA) and the American College of Cardiology (ACC) have partnered with other organizations to translate the best available scientific evidence into clinical practice guidelines (CPGs) for cardiovascular conditions. These efforts reflect a shared vision and responsibility for using scientific evidence and the expert clinical opinion of leaders in the field to develop recommendations for healthcare providers. These CPGs, based on systematic methods to evaluate and classify evidence, have provided the cornerstones for delivering quality cardiovascular care. CPGs are essential tools for optimizing care for patients with cardiovascular conditions. Enhancing the utility of CPGs requires that the development process reflect the evolution of relevant foundational domains, such as biomedical discoveries, public policy, clinical care systems, and epidemiological knowledge. Dynamic changes in these domains pose substantial implications for organizations that develop CPGs. Among these changes is the increasing prevalence of ≥2 chronic conditions among individual Americans, estimated to be present in more than one quarter of adults.4 In the large population of Medicare beneficiaries, the prevalence of persons with multiple chronic conditions is considerably greater: more than two thirds (68%) have ≥2 chronic conditions, and 14% have ≥6 chronic conditions.5,6 CPGs jointly developed by the AHA/ACC are cardiovascular disease-specific documents focused on the prevention, diagnosis, and management of conditions such as ischemic heart disease, heart failure, and atrial fibrillation. These CPGs often contain considerations for special factors (eg, older adults) and common problems affecting pharmacokinetics (eg, renal impairment). For example, the 2014 CPG on atrial fibrillation7 highlights special considerations for acute myocardial infarction, pregnancy, hyperthyroidism, and other conditions. With the exception of the CPGs on …

Lipoprotein subfractions help discriminate cardiometabolic disease risk. Genetic loci validated as associating with lipoprotein measures do not account for a large proportion of the individual variation in lipoprotein measures. We hypothesized that DNA methylation levels across the genome contribute to interindividual variation in lipoprotein measures. Using data from participants of the Genetics of Lipid Lowering Drugs and Diet Network (n = 663 for discovery and n = 331 for replication stages, respectively), we conducted the first systematic screen of the genome to determine associations between methylation status at ∼470,000 cytosine-guanine dinucleotide (CpG) sites in CD4(+) T cells and 14 lipoprotein subfraction measures. We modeled associations between methylation at each CpG site and each lipoprotein measure separately using linear mixed models, adjusted for age, sex, study site, cell purity, and family structure. We identified two CpGs, both in the carnitine palmitoyltransferase-1A (CPT1A) gene, which reached significant levels of association with VLDL and LDL subfraction parameters in both discovery and replication phases (P < 1.1 × 10(-7) in the discovery phase, P < .004 in the replication phase, and P < 1.1 × 10(-12) in the full sample). CPT1A is regulated by PPARα, a ligand for drugs used to reduce CVD. Our associations between methylation in CPT1A and lipoprotein measures highlight the epigenetic role of this gene in metabolic dysfunction.

Summary Background and aims Eggs are a ubiquitous and important source of dietary cholesterol and nutrients, yet their relationship to coronary heart disease (CHD) remains unclear. While some data have suggested a positive association between egg consumption and CHD, especially among diabetic subjects, limited data exist on the influence of egg consumption on subclinical disease. Thus, we sought to examine whether egg consumption is associated with calcified atherosclerotic plaques in the coronary arteries. Methods In a cross-sectional design, we studied 1848 participants of the NHLBI Family Heart Study without known CHD. Egg consumption was assessed by a semi-quantitative food frequency questionnaire and coronary-artery calcium (CAC) was measured by cardiac CT. We defined prevalent CAC using an Agatston score of at least 100 and fitted generalized estimating equations to calculate prevalence odds ratios of CAC. Results Mean age was 56.5 years and 41% were male. Median consumption of eggs was 1/week. There was no association between frequency of egg consumption and prevalent CAC. Odds ratios (95% CI) for CAC were 1.0 (reference), 0.95 (0.66–1.38), 0.94 (0.63–1.40), and 0.90 (0.57–1.42) for egg consumption of almost never, 1–3 times per month, once per week, and 2+ times per week, respectively ( p for trend 0.66), adjusting for age, sex, BMI, smoking, alcohol, physical activity, income, field center, total calories, and bacon. Additional control for hypertension and diabetes mellitus, or restricting the analysis to subjects with diabetes mellitus or fasting glucose >126 mg/dL did not alter the findings. Conclusions These data do not provide evidence for an association between egg consumption and prevalent CAC in adult men and women.

The interaction between a functional apolipoprotein A2 gene (APOA2) variant and saturated fatty acids (SFAs) for the outcome of body mass index (BMI) is among the most widely replicated gene-nutrient interactions. Whether this interaction can be extrapolated to food-based sources of SFAs, specifically dairy foods, is unexplored. Cross-sectional analyses were performed in 2 U.S. population–based samples. We evaluated interactions between dairy foods and APOA2 −265T > C (rs5082) for BMI in the Boston Puerto Rican Health Study (n = 955) and tested for replication in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study (n = 1116). Dairy products were evaluated as total dairy, higher-fat dairy (>1%), and low-fat dairy (≤1%) in servings per day, dichotomized into high and low based on each population median and also as continuous variables. We identified a statistically significant interaction between the APOA2 −265T > C variant and higher-fat dairy food intake in the Boston Puerto Ricans (P-interaction = 0.028) and replicated this relation in the GOLDN study (P-interaction = 0.001). In both groups, individuals with the previously demonstrated SFA-sensitive genotype (CC) who consumed a greater amount of higher-fat dairy foods had greater BMI (P = 0.013 in Boston Puerto Ricans; P = 0.0007 in GOLDN women) compared with those consuming less of the higher-fat dairy foods. The results expand the understanding of the metabolic influence of dairy products, an important food group for which variable relations to body weight may be in part genetically based. Moreover, these findings suggest that other strongly demonstrated gene-nutrient relations might be investigated through appropriate food-based, translatable avenues and may be relevant to dietary management of obesity.

In recent years, an important conceptual shift has emerged among epidemiologists and prevention experts in the quest to reduce morbidity and mortality caused by cardiovascular disease (CVD). Historically we have fixed our gaze on death and disease and designed public health efforts that worked

Alice K. Jacobs, MD, FACC, FAHA, Immediate Past Chair Jeffrey L. Anderson, MD, FACC, FAHA, Chair Jonathan L. Halperin, MD, FACC, FAHA, Chair-Elect Nancy M. Albert, PhD, CCNS, CCRN, FAHA Mark A. Creager, MD, FACC, FAHA David L. DeMets, PhD Steven M. Ettinger, MD, FACC Robert A. Guyton, MD

Macronutrient intakes and genetic variants have been shown to interact to alter the risk of insulin resistance, but replication of gene-nutrient interactions across independent populations may be difficult to achieve. Saturated fat and carbohydrate were previously shown to interact with genotype for insulin resistance for a variant of perilipin (PLIN), the major adipocyte-associated protein and a regulator of adipocyte metabolism. We investigated the same interaction for PLIN 11482G>A (rs894160) on insulin resistance in US men(n=462) and women(n=508) (mean ±SD, 49±16 years). In multivariate linear regression models, we found a significant (PA for HOMA-IR (homeostasis model assessment of insulin resistance) in women. For carriers of the minor allele but not for non-carriers, as the ratio of saturated fat to carbohydrate intake increased, predicted HOMA-IR increased significantly (P=0.002). By dichotomizing the ratio of saturated fat to carbohydrate intake into high and low, we found significant interaction terms for insulin and HOMA-IR (P

High levels of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) are associated with inflammation, atherosclerosis, and coronary heart disease events. In addition, Lp-PLA(2) has been linked to classical markers of endothelial activation, including soluble vascular cell adhesion molecule-1 (sVCAM-1). Although treatment with fenofibrate reduces Lp-PLA(2) mass, it is unclear whether fenofibrate reduces sVCAM-1 levels or whether an association exists between any changes observed in Lp-PLA(2) and sVCAM-1. Concentrations of Lp-PLA(2) mass and sVCAM-1 levels were measured in plasma at baseline and after 3 weeks of fenofibrate treatment (160 mg/d) in 96 hypertriglyceridemic participants of the Genetics of Lipid-lowering Drugs and Diet Network study. Lp-PLA(2) and sVCAM-1 were stratified by tertiles as determined by baseline levels of the respective target. Fenofibrate treatment resulted in a 30.1% mean increase in Lp-PLA(2) mass (P = 0.0003) and a 14.7% mean increase in sVCAM-1 levels (P = 0.0096) but only in tertile1 of either target. In contrast, Lp-PLA(2) mass was reduced by 35.3% (P0.0001) in tertile 3. Soluble VCAM-1 levels were significantly reduced by 7.74% (P = 0.0109) and 17.2% (P0.0001) in tertiles 2 and 3, respectively. No associations were observed between Lp-PLA(2) and sVCAM-1 at baseline or post-treatment. In conclusion, fenofibrate treatment in hypertriglyceridemic subjects reduced the levels of Lp-PLA(2) mass and sVCAM-1, but only in those with elevated baseline levels of these biomarkers. The greatest reductions in Lp-PLA(2) levels were observed in individuals with Lp-PLA(2) concentrations indicative of increased cardiovascular disease risk (200 ng/mL).

Epidemiologic studies have suggested beneficial effects of flavonoids on cardiovascular disease. Cocoa and particularly dark chocolate are rich in flavonoids and recent studies have demonstrated blood pressure lowering effects of dark chocolate. However, limited data are available on the association of chocolate consumption and the risk of coronary heart disease (CHD). We sought to examine the association between chocolate consumption and prevalent CHD.We studied in a cross-sectional design 4970 participants aged 25-93 years who participated in the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study. Chocolate intake was assessed through a semi-quantitative food frequency questionnaire. We used generalized estimating equations to estimate adjusted odds ratios.Compared to subjects who did not report any chocolate intake, odds ratios (95% CI) for CHD were 1.01 (0.76-1.37), 0.74 (0.56-0.98), and 0.43 (0.28-0.67) for subjects consuming 1-3 times/month, 1-4 times/week, and 5+ times/week, respectively (p for trend0.0001) adjusting for age, sex, family CHD risk group, energy intake, education, non-chocolate candy intake, linolenic acid intake, smoking, alcohol intake, exercise, and fruit and vegetables. Consumption of non-chocolate candy was associated with a 49% higher prevalence of CHD comparing 5+/week vs. 0/week [OR = 1.49 (0.96-2.32)].These data suggest that consumption of chocolate is inversely related with prevalent CHD in a general United States population.

Context The literature predominately describes hospice utilization among Medicare recipients, with a limited number of reports describing use among all age groups. Objectives This study aimed to describe and compare patterns of hospice use among decedents of all ages in Alabama using a population-based approach. Methods We obtained death certificates for Alabama residents who died from January 1, 2002 to December 31, 2005 (n=178,420). To ascertain hospice use, we linked death certificates to the hospice administering care using state-mandated listings of deaths reported by hospices. Additionally, each decedent's residence at death was geocoded and area-level socioeconomic status (SES) measures were added. Results From 2002 to 2005, a total of 43,638 Alabamians died while under hospice care, representing a quarter (24.5%) of all deaths in the state. During this four-year span, the rate of hospice use increased by nearly 15% (22.2%–25.6%). As expected, rates of hospice use increased with age at death. For the SES indicators for poverty, education, and income, rates of hospice use increased as SES improved. However, this pattern was found to vary by race and metro/nonmetro status. Conclusions In addition to revealing racial, geographic, and other disparities in hospice care across Alabama, our results indicate usage rates in Alabama trail behind those observed nationally. We also identified previously unreported interactions between race, urbanization level, and poverty classification. Future studies should explore whether such relationships exist elsewhere and the rationale for their occurrence.

summary Background & aims: While a diet rich in anti-oxidant has been favorably associated with coronary disease and hypertension, limited data have evaluated the influence of such diet on subclinical disease. Thus, we sought to examine whether chocolate consumption is associated with calcified atherosclerotic plaque in the coronary arteries (CAC). Methods: In a cross-sectional design, we studied 2217 participants of the NHLBI Family Heart Study. Chocolate consumption was assessed by a semi-quantitative food frequency questionnaire and CAC was measured by cardiac CT. We defined prevalent CAC using an Agatston score of at least 100 and fitted generalized estimating equations to calculate prevalence odds ratios of CAC. Results: There was an inverse association between frequency of chocolate consumption and prevalent CAC. Odds ratios (95% CI) for CAC were 1.0 (reference), 0.94 (0.66e1.35), 0.78 (0.53e1.13), and 0.68 (0.48e0.97) for chocolate consumption of 0, 1e3 times per month, once per week, and 2þ times per week, respectively (p for trend 0.022), adjusting for age, sex, energy intake, waist-hip ratio, education, smoking, alcohol consumption, ratio of total-to-HDL-cholesterol, non-chocolate candy, and diabetes mellitus. Controlling for additional confounders did not alter the findings. Exclusion of subjects with coronary heart disease or diabetes mellitus did not materially change the odds ratio estimates but did modestly decrease the overall significance (p ¼ 0.07). Conclusions: These data suggest that chocolate consumption might be inversely associated with prevalent

Hypertriglyceridemia, defined as a triglyceride measurement > 150 mg/dl, occurs in up to 34% of adults. Fenofibrate is a commonly used drug to treat hypertriglyceridemia, but response to fenofibrate varies considerably among individuals. We sought to determine if genetic variation in apolipoprotein B (APOB), an essential core of triglyceride-rich lipoprotein formation, may account for some of the inter-individual differences observed in triglyceride (TG) response to fenofibrate treatment. Participants (N = 958) from the Genetics of Lipid Lowering Drugs and Diet Network study completed a three-week intervention with fenofibrate 160 mg/day. Associations of four APOB gene single nucleotide polymorphisms (SNP) (rs934197, rs693, rs676210, and rs1042031) were tested for association with the TG response to fenofibrate using a mixed growth curve model where the familial structure was modeled as a random effect and cardiovascular risk factors were included as covariates. Three of these four SNPs changed the amino acid sequence of APOB, and the fourth was in the promoter region. TG response to fenofibrate treatment was associated with one APOB SNP, rs676210 (Pro2739Leu), such that participants with the TT genotype of rs676210 had greater TG lowering than those with the CC genotype (additive model, P = 0.0017). We conclude the rs676210 variant may identify individuals who respond best to fenofibrate for TG reduction.

The association between hyperuricemia and incident heart failure (HF) is relatively unknown.Of the 5461 community-dwelling older adults,or=65 years, in the Cardiovascular Health Study without HF at baseline, 1505 had hyperuricemia (baseline serum uric acidor=6 mg/dL for women andor=7 mg/dL for men). Using propensity scores for hyperuricemia, estimated for each participant using 64 baseline covariates, we were able to match 1181 pairs of participants with and without hyperuricemia.Incident HF occurred in 21% and 18% of participants respectively with and without hyperuricemia during 8.1 years of mean follow-up (hazard ratio {HR} for hyperuricemia versus no hyperuricemia, 1.30; 95% confidence interval {CI}, 1.05-1.60; P=0.015). The association between hyperuricemia and incident HF was significant only in subgroups with normal kidney function (HR, 1.23; 95% CI, 1.02-1.49; P=0.031), without hypertension (HR, 1.31; 95% CI, 1.03-1.66; P=0.030), not receiving thiazide diuretics (HR, 1.20; 95% CI, 1.01-1.42; P=0.044), and without hyperinsulinemia (HR, 1.35; 95% CI, 1.06-1.72; P=0.013). Used as a continuous variable, each 1 mg/dL increase in serum uric acid was associated with a 12% increase in incident HF (HR, 1.12; 95% CI, 1.03-1.22; P=0.006). Hyperuricemia had no association with acute myocardial infarction or all-cause mortality.Hyperuricemia is associated with incident HF in community-dwelling older adults. Cumulative data from our subgroup analyses suggest that this association is only significant when hyperuricemia is a marker of increased xanthine oxidase activity but not when hyperuricemia is caused by impaired renal elimination of uric acid.

Plasma high density lipoprotein (HDL) cholesterol (HDL-C) concentration is highly heritable but is also modifiable by environmental factors including physical activity. HDL-C response to exercise varies among individuals, and this variability may be associated with genetic polymorphisms in the key regulators of HDL metabolism including endothelial lipase (LIPG).We examined associations between variants LIPG T111I (rs2000813) and LIPG i24582 (rs6507931), HDL and television viewing/computer use ("screen time") as a marker for physical inactivity in a population with high prevalence of metabolic syndrome. Subjects consisted of 539 White men and 584 women (mean+/-S.D., 49+/-16 years) participating in the GOLDN study.We did not observe an association with either LIPG SNP or HDL independently of screen time. In multi-adjusted linear regression models, HDL interacted significantly with screen time as a continuous variable in LIPG i24582 subjects with TT genotype (P0.05). By dichotomizing screen time into high and low levels, we found significant genotype-associated differences in HDL in women but not men. When screen time wasor=2.6h/day, the concentrations of total HDL-C, large HDL, large low density lipoprotein (LDL) were lower, the concentration of small LDL was higher and HDL and LDL particle sizes were smaller in subjects with LIPG i24582 TT compared to CT and CC subjects (P0.05).We found a significant gene-physical inactivity interaction for HDL and some LDL measures for the LIPG i24582 polymorphism. Higher levels of physical activity may be protective for HDL-C concentrations and low activity detrimental in LIPG i24582 TT individuals, especially in women.

The scaffolding protein PDZ domain containing 1 (PDZK1) regulates the HDL receptor scavenger receptor class B type I. However, the effect of PDZK1 genetic variants on lipids and metabolic syndrome (MetS) traits remains unknown. This study evaluated the association of 3 PDZK1 single nucleotide polymorphisms (SNP) (i33968C > T, i15371G > A, and i19738C > T) with lipids and risk of MetS and their potential interactions with diet. PDZK1 SNP were genotyped in 1000 participants (481 men, 519 women) included in the Genetics of Lipid Lowering Drugs and Diet Network study. Lipoprotein subfractions were measured by proton NMR spectroscopy and dietary intake was estimated using a validated questionnaire. The PDZK1_i33968C > T polymorphism was associated with MetS (P = 0.034), mainly driven by the association of the minor T allele with higher plasma triglycerides (P = 0.004) and VLDL (P = 0.021), and lower adiponectin concentrations (P = 0.022) than in participants homozygous for the major allele (C). We found a significant gene x BMI x diet interaction, in which the deleterious association of the i33968T allele with MetS was observed in obese participants with high PUFA and carbohydrate (P-values ranging from 0.004 to 0.020) intakes. Conversely, a there was a protective effect in nonobese participants with high PUFA intake (P T genetic variants may be associated with a higher risk of exhibiting MetS. This gene x BMI x diet interaction offers the potential to identify dietary and other lifestyle changes that may obviate the onset of MetS in individuals with a specific genetic background.

Background Smoking is associated with increased postprandial hypertriglyceridemia (PPT). Inflammation and insulin resistance are potential “drivers” for this phenomenon. We tested whether inflammatory patterns and/or insulin resistance explain the effect of smoking on PPT.

Background Recent work has demonstrated a link between retinopathy, a marker of microvascular disease, and the development of heart failure, a finding particularly relevant in individuals with diabetes. Our objective was to assess the relationship between retinopathy and cardiac structure and function in a cohort of individuals with type 2 diabetes mellitus. Methods Stereoscopic fundus photography of 7 standard fields was obtained in 531 Mexican American adults with type 2 diabetes mellitus recruited as sibships from Starr County, Texas. Retinopathy was centrally scored and classified as no retinopathy, early nonproliferative diabetic retinopathy, moderate to severe nonproliferative diabetic retinopathy, or proliferative diabetic retinopathy. Echocardiography was used to assess cardiac structure and function. Multilevel mixed models were used to assess associations of clinical and echocardiographic variables with retinopathy while accounting for correlations among siblings. Results More severe diabetic retinopathy was associated with the presence of hypertension, previous cardiovascular disease, longer duration of diabetes, elevated glycosylated hemoglobin, and greater albuminuria. With worsening severity of diabetic retinopathy, left ventricular (LV) mass and left atrial dimension increased, and LV ejection fraction and LV fractional shortening decreased, independent of potential confounding variables. Conclusions More severe diabetic retinopathy was associated with worse cardiac structure and function by echocardiography independent of potential confounding variables. These data suggest a possible microvascular contribution to the development of diabetes-associated cardiac enlargement and dysfunction. Alternatively, common pathways may be leading to both disorders.

The transcription factor 7-like 2 (TCF7L2) has been recently associated with diabetes risk, and it may exert its effect through metabolic syndrome (MetS)-related traits and be subjected to modification by environmental factors. We investigated the effect of single nucleotide polymorphisms (SNP), rs7903146 and rs12255372, within the TCF7L2 locus on postprandial lipemia and other MetS-related traits and their modulation by dietary fat. Data were collected from 1083 European Americans participating in the Genetics of Lipid Lowering Drugs and Diet Network Study. Carriers of the minor T allele at the C/T rs7903146 SNP had higher fasting plasma glucose (P = 0.012), lower homeostasis model assessment of beta cell function (P = 0.041), higher plasma VLDL (P = 0.035), and lower large LDL particle (P = 0.007) concentrations and higher risk of MetS (P = 0.011) than CC individuals. Moreover, we identified significant interactions between this SNP and PUFA intake modulating fasting VLDL particle concentrations (P = 0.016) and postprandial triglycerides (TG) (P = 0.028), chylomicrons (P = 0.025), total VLDL (P = 0.026), and large VLDL (P = 0.018) concentrations. Thus, only T allele carriers with a PUFA intake > or = 7.36% of energy had elevated fasting plasma VLDL concentrations and postprandial TG-rich lipoproteins. These variables did not differ in T allele carriers and noncarriers in the low-PUFA intake group. Moreover, these significant interactions were due exclusively to (n-6) PUFA intake. In summary, high (n-6) PUFA intakes (> or = 6.62% of energy intake) were associated with atherogenic dyslipidemia in carriers of the minor T allele at the TCF7L2 rs7903146 SNP and may predispose them to MetS, diabetes, and cardiovascular disease.

Atherogenesis is a chronic inflammatory process in which intercellular adhesion molecule 1 (ICAM-1) plays a critical role. Circulating soluble ICAM-1 (sICAM-1) is thought to be the result of cleavage of membrane-bound ICAM-1 and its concentration in serum/plasma has been shown to be heritable. Genome-wide linkage scans were conducted for quantitative trait loci influencing sICAM-1. Phenotype and genetic marker data were available for 2,617 white and 531 black individuals in the NHLBI Family Heart Study follow-up examination. Heritability for sICAM-1 was 0.39 in whites and 0.59 in blacks. Significant linkage was observed on chromosome 19 (LOD = 4.0 at 14 cM) in whites near the ICAM gene cluster that includes the structural gene for ICAM-1. The T-allele of ICAM-1 SNP rs5491 has been strongly associated with the specific sICAM-1 assay we used in our study. Through additional genotyping we were able to rule out rs5491 as the cause of the linkage finding. This study provides preliminary evidence linking genetic variation in the ICAM-1 structural gene to circulating sICAM-1 levels.

BACKGROUND Several perilipin (PLIN) polymorphic sites have been studied for their potential use as markers for obesity and the metabolic syndrome. OBJECTIVE We aimed to examine whether the presence of polymorphisms at the perilipin (PLIN) locus (PLIN1, 6209T-->C; PLIN4, 11482G-->A; PLIN5, 13041A-->G; and PLIN6, 14995A-->T) influence postprandial lipoprotein metabolism in 2 white populations. DESIGN Eighty-eight healthy Spanish men and 271 healthy US subjects (men and women) underwent an oral-fat-load test in 2 independent studies. Blood samples were taken in the fasting state and during the postprandial phase at regular intervals. Total cholesterol and triacylglycerol and triacylglycerol in triacylglycerol-rich lipoproteins (TRL, large and small) were measured. RESULTS Carriers of the minor C allele at the PLIN1 variant displayed lower postprandial concentrations of large-TRL triacylglycerol (Spanish subjects: P = 0.024; US subjects: P = 0.005) than did subjects carrying the T/T genotype. The same pattern was observed in the Spanish population at the PLIN4 locus (P = 0.015), and both SNPs were in strong linkage disequilibrium. In both populations, subjects carrying the minor C and A alleles at PLIN1 and PLIN4, respectively, had significantly lower postprandial concentrations of plasma triacylglycerol (P < 0.05) and lower concentrations of small-TRL triacylglycerol than did those who were homozygous for the major alleles at PLIN1 and PLIN4 (Spanish subjects: P = 0.020 and 0.008, respectively; US subjects: P = 0.021 and 0.035, respectively). CONCLUSION These 2 studies suggest that the presence of the minor C and A alleles at PLIN1 and PLIN4, respectively, are associated with a lower postprandial response that may result in lower atherogenic risk for these persons.

C-reactive protein (CRP) or coronary artery calcium (CAC) score have been suggested to identify a higher risk subset of intermediate-risk individuals, who potentially could be considered for more aggressive therapy. In the Multi-Ethnic Study of Atherosclerosis (MESA), we estimated the proportion of intermediate-risk participants whose risk status might change based on additional testing using CRP and/or CAC score.Framingham 10-year CHD risk scores (FRS) were calculated and cross tabulations were used to determine the percent of individuals at intermediate-risk by FRS with a CRP3mg/L and/or CAC score100 AU. Similar analyses were performed using the gender-specific 75th percentile for CRP and CAC.Of the 30% of participants (N=1450) classified as intermediate-risk by FRS, 30% had a CRP3mg/L and 33% had a CAC score100 AU. Among intermediate-risk women, 49% had a CRP3mg/L compared to 27% of intermediate-risk men (p0.0001) while the same percent of intermediate-risk women and men (33%) had a CAC score100 AU. Eleven percent or less of men or women had both a high CRP and CAC score whether conventional or gender-specific cut points were used. When the percent of intermediate-risk individuals with an elevated CRP and/or CAC score in MESA were applied to NHANES III data, over a million intermediate-risk individuals would move to high risk status if CRP or CAC screening directed treatment strategies were uniformly adopted in the U.S.There were differences in the number of intermediate-risk individuals reclassified as high risk depending on the screening test used, the cut points selected, and the demographics of the individuals being screened. These data highlight current limitations of broadly using risk markers such as CRP and CAC score in an intermediate-risk population.

Chronic inflammation has been identified as an important component of the metabolic syndrome (MetS). Therefore, environmental and genetic factors contributing to the variation of inflammatory responses could affect individuals' susceptibility to MetS. We investigated the association between common IL1beta genetic polymorphisms, inflammation, and the MetS, and the modulation of diet-related variables (i.e., erythrocyte membrane fatty acid composition) in a white U.S. population. IL1beta single nucleotide polymorphisms (SNP) (-1473G > C, -511G > A, -31T > C, 3966C > T, 6054G > A), clinical and biochemical measurements were characterized in a total of 1120 subjects (540 males and 580 females) participating in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study. The 6054 G > A SNP was significantly associated with plasma C-reactive protein (P = 0.054), adiponectin (P = 0.021), and the prevalence of MetS (P = 0.004). Moreover, there was a significant interaction between the 6054G > A SNP and erythrocyte membrane (n-3) PUFA (P = 0.019). Among subjects with low (n-3) PUFA content (below the median), the 6054 G allele was associated with increased risk of the MetS (OR = 3.29, 95%CI = 1.49-7.26 for GG and OR = 1.95, 95%CI = 0.85-4.46 for GA, P < 0.001) compared with the AA genotype, but there were no significant genotype associations among subjects with high (n-3) PUFA content (above the median). Further analyses supported a significant haplotype global effect on the MetS (P = 0.017) among subjects with low (n-3) PUFA content. These results suggested that IL1beta genetic variants were associated with measures of chronic inflammation and the MetS risk, and that genetic influences were more evident among subjects with low (n-3) PUFA intake.

Background The distribution and determinants of left ventricular (LV) geometric patterns and their relation to LV function in African Americans is not well described despite higher rates of LV hypertrophy and cardiovascular mortality reported in this group. Purpose This study investigates the distribution and clinical correlates of LV geometric patterns and how these patterns relate to function in a population-based African American cohort. Methods The study population included participants in the Jackson cohort of ARIC, who underwent echocardiograms between 1993 and 1995. We defined 4 geometric patterns (normal geometry, concentric remodeling [CR], eccentric hypertrophy [EH], and concentric hypertrophy [CH]) according to LV mass index and relative wall thickness. Multiple logistic regression was used to assess the association of geometric patterns to systolic dysfunction and diastolic dysfunction, adjusting for traditional coronary risk factors. Results There were 1849 participants in the study population (mean age 59 years, 65% women). Concentric remodeling and CH were highly prevalent. Concentric hypertrophy and EH groups had the highest rates of hypertension, obesity, and diabetes mellitus. Compared to the normal geometric pattern, EH was related to systolic dysfunction (OR 24.27, CI 6.71-87.80), and CH was related to diastolic dysfunction 1.58 (1.04-2.39). Concentric remodeling was not related to systolic or diastolic dysfunction. Conclusion In this large middle-aged African American cohort, CR and CH are prevalent. Hypertension, diabetes mellitus, and obesity are associated with both CH and EH. Concentric hypertrophy is strongly associated with diastolic dysfunction; EH is strongly associated with systolic dysfunction. Concentric remodeling, however, is not related to either systolic or diastolic dysfunction.

Background The aim of this study was to determine whether the angiotensin-converting enzyme (ACE) insertion-deletion (ID) polymorphism interacts with pravastatin to modify the risk of coronary heart disease (CHD) and other cardiovascular end points in a large clinical trial. Methods GenHAT is an ancillary study of the ALLHAT. The ACE ID genotyped population in the lipid-lowering arm of ALLHAT included 9467 participants randomly assigned to pravastatin (n = 4741) or to usual care (n = 4726). The efficacy of pravastatin in reducing the risk of primary outcome (all-cause mortality) and secondary outcomes (fatal CHD and nonfatal myocardial infarction, cardiovascular disease [CVD] mortality, CHD, stroke, other CVD, non-CVD mortality, stroke, and heart failure) was compared between the genotype strata (dominant model ID + II vs DD, additive model II vs ID vs DD), by examining an interaction term in a Cox proportional hazards model. Results The relative risk of fatal CHD and nonfatal myocardial infarction among subjects randomized to pravastatin compared with subjects randomized to usual care was similar in subjects with the II genotype (hazard ratio [HR] 0.84, 95% CI 0.59-1.18), the ID genotype (HR 0.84, 95% CI 0.68-1.03), and the DD genotype (HR 0.99, 95% CI 0.77-1.27). Conclusions We found no evidence that the ACE ID genotype was a major modifier of the efficacy of pravastatin in reducing the risk of cardiovascular events.

Although recent data suggest that the mitral diastolic early-to-late (E/A) ratio may be prognostic in selected population-based cohorts, its predictive value for morbidity and mortality in African Americans has not yet been well studied.The study population consisted of African American participants from the Jackson cohort of the Atherosclerotic Risks in Community Study. Three subgroups of E/A ratios were defined: E/A0.7, E/A 0.7-1.5, and E/A1.5, using the middle group as reference. Cox proportional hazard models were used to assess the association between the E/A ratio and both all-cause mortality and incident cardiovascular disease (CVD). The mean follow-up period was 6.8 +/- 1.3 years.Of the 2211 participants in the study population (mean age 62 years, 65.1% women), 8.2% had an E/A ratio0.7, 84.7% had an E/A 0.7-1.5, and 7.1% had an E/A1.5. An E/A1.5 was independently associated with all-cause mortality (hazard ratio [HR] 2.18, 95% confidence interval [CI] 1.20-4.03) in the multivariable model. An E/A0.7 was associated with higher all-cause mortality (HR 1.79, 95% CI 1.17-2.73) and incident CVD (HR 1.91, 95% CI 1.29-2.83) compared with a normal E/A in the age and sex adjusted model but was not independently predictive in the multivariable model (P.05).In a population-based cohort of middle-aged African Americans, an E/A1.5 independently predicts all-cause mortality. An E/A1.5 and an E/A0.7 were both associated with incident CVD when adjusted for age and sex alone but were not independently predictive in the multivariable analysis.

Studies have reported a lower burden of calcified atherosclerotic plaque in coronary arteries in African-Americans than in whites. Findings from autopsy studies of sudden cardiac death have suggested a link between left ventricular hypertrophy and severity of coronary atherosclerosis. Echocardiograms and cardiac computed tomograms were analyzed in 334 African-American (84% hypertensive) and 196 white (66% hypertensive) adults with no history of coronary heart disease or revascularization procedures at study entry. The relation of coronary artery calcium (CAC) score to left ventricular mass and left ventricular mass indexed to body surface area was assessed by Spearman's correlations and mixed linear models. Covariates included age, gender, field center, weight, height, systolic blood pressure, number of antihypertensive medications, diabetes, total and high-density lipoprotein cholesterol levels, and current smoking and alcohol consumption. In African-Americans, a significant and independent association between CAC score and left ventricular mass or left ventricular mass indexed to body surface area was present with the 2 analytic strategies. Spearman's correlation coefficients for CAC score with left ventricular mass and left ventricular mass indexed to body surface area were 0.14 (p = 0.015) and 0.13 (p = 0.025), respectively, after multivariable adjustment. In whites, the associations of CAC score with measurements of left ventricular mass were weaker and only marginally significant in mixed linear models. In conclusion, these findings suggest that CAC reflects a different risk burden between African-Americans and whites, and future studies examining the prognostic implications of CAC in African-Americans should consider the potential association between CAC and left ventricular hypertrophy.

Objectives This study sought to test the hypothesis that reduced regional left ventricular (LV) function is associated with traditional risk factors including hypertension, hypercholesterolemia, and smoking in asymptomatic individuals. Background Coronary artery disease is the main etiology of congestive heart failure in the U.S. and Europe. However, the relationship between risk factors for coronary artery disease and decreased myocardial function has not been studied systematically in asymptomatic individuals. Methods The Multi-Ethnic Study of Atherosclerosis (MESA) is a cohort study designed to investigate the nature of atherosclerosis in asymptomatic individuals. A total of 1,184 participants (45 to 84 years old) underwent tagged cardiac magnetic resonance imaging. Regional LV function was quantified by analyzing peak systolic circumferential strain (Ecc) in regions corresponding to the left anterior descending (LAD), circumflex (LCX), and right coronary (RCA) territories. The association between risk factors and strains was studied using multiple linear regression. Results Higher diastolic blood pressure (DBP) was associated with lower Ecc (p ≤ 0.002). The Ecc’s in the LAD territory of participants with DBP Conclusions Higher diastolic blood pressure and smoking are associated with decreased regional LV function in asymptomatic individuals.

Nonprescription products (over-the-counter drugs; vitamins/minerals; and nonvitamin, nonmineral supplements) are promoted or advertised for cardiovascular health. The extent of nonprescription products used specifically for perceived cardiovascular health (NONRX-CVH) is unknown. This study aimed to (1) determine prevalence and types of nonprescription medications used for NONRX-CVH, (2) compare the demographics of NONRX-CVH users to persons using nonprescription medications in general, and (3) determine the prevalence of use of NONRX-CVH among those taking a prescription medication for a cardiovascular reason.A cross-sectional survey comprised the probability sample of 3128 adults in the Minneapolis-St. Paul area in the 2000-2002 Minnesota Heart Survey. Trained interviewers collected medication information from participants using a structured medication inventory approach.Analysis in 2005 shows that 10% of participants (n=315) self-reported taking one or more nonprescription medications in the past 2 weeks for a perceived cardiovascular health purpose. Among these individuals, prevalence of use of vitamin/mineral supplements, nonvitamin/nonmineral supplements, and over-the-counter products for a cardiovascular purpose was 37.5%, 21.3%, and 54.6%, respectively. Popular NONRX-CVHs were aspirin (52.1%), vitamin E (24.4%), garlic (9.8%), and omega-3/fish oils/fatty acids (3.8%). NONRX-CVH users were older than general nonprescription users (p0.001). Of 613 people using a prescription drug for cardiovascular reasons, 135 (22%) reported using one or more NONRX-CVH medications.Use of NONRX-CVHs, especially aspirin, vitamin E, and herbals, is common, and older patients may use aspirin or dietary supplements for this purpose. Physicians having patients with cardiovascular disease should ask about nonprescription medication usage, as some NONRX-CVHs may be inappropriate.

Exaggerated blood pressure (BP) reactivity to stress may contribute to left ventricular (LV) hypertrophy, a major risk factor for cardiovascular morbidity. This study examined the extent to which BP responses to acute stress are associated with LV mass and relative wall thickness in a community sample of African-American and white men and women. BP was measured at rest and in response to 2 acute challenges (mental arithmetic and handgrip). Systolic BP at rest was positively associated with LV mass and relative wall thickness (p0.001). The associations between the responses to the stressors and LV mass were not significant. African-American and white men who exhibited high BP responses to the arithmetic stressor had greater relative wall thickness than those with low reactivity (p0.05). In conclusion, BP reactivity is not related to LV mass, but may be related to concentric remodeling.

Despite wide use of the influenza vaccine, relatively little is known about its effect on the measurement of inflammatory markers. Because inflammatory markers such as C-reactive protein (CRP) are increasingly being used in conjunction with lipids for the clinical assessment of cardiovascular disease and in epidemiologic studies, we evaluated the effect of influenza vaccination on markers of inflammation and plasma lipid concentrations. We drew blood from 22 healthy individuals 1 to 6 hours before they were given an influenza vaccination and 1, 3, and 7 days after the vaccination. Plasma CRP, interleukin (IL)-6, monocyte chemotactic protein 1, tumor necrosis factor alpha, IL-2 soluble receptor alpha, and serum amyloid A were measured, and differences in mean concentrations of absolute and normalized values on days 1, 3, and 7 were compared with mean baseline values. There was a significant increase in mean IL-6 (P.01 absolute values, P.001 normalized values) on day 1 after receiving the influenza vaccine. The mean increases in normalized high sensitivity CRP values were significant on day 1 (P.01) and day 3 (P = .05), whereas the mean increase in normalized serum amyloid A was significant only on day 1 (P.05). No significant changes were seen in mean concentrations of IL-2 soluble receptor alpha, monocyte chemotactic protein-1, or tumor necrosis factor-alpha. Of the lipids, significant decreases in mean concentrations of normalized triglyceride values were seen on days 1 (P.05), 3 (P.001), and 7 (P.05) after vaccination. Our findings show that the influenza vaccination causes transient changes in select markers of inflammation and lipids. Consequently, clinical and epidemiologic interpretation of the biomarkers affected should take into account the possible effects of influenza vaccination.

Background We have shown that increased cardiac output is related to both fat-free mass and fat mass in obesity. Objective We studied the association of body fat distribution and body composition with flow-resistance relations in overweight. Design We studied 521 overweight, nonobese participants in the Hypertension Genetic Epidemiology Network (HyperGEN) Study-a component of the National Heart, Lung, and Blood Institute Family Blood Pressure Program, designed to assess the genetic basis of hypertension. Participants had normal ventricular function and no cardiovascular disease: 261 with central fat distribution (CFD) (waist girth >88 cm in women and >102 cm in men) and 260 with peripheral fat distribution (PFD). Fat-free mass (FFM) and fat mass (FM) were measured by bioelectric impedance. Body composition was estimated as FM/FFM. Echocardiographic stroke volume (SV) and cardiac output (CO) were measured. Results Hypertension was present in 73% of the subjects with PFD and in 78% with CFD. Overweight with CFD was associated with greater FM/FFM in both normotensive and hypertensive participants. After FFM, age, sex, and race were controlled for, SV and CO were higher in subjects overweight with CFD than in those with PFD, whereas peripheral resistance was not significantly different. Differences in CO between CFD and PFD were reduced after further adjustment for FM. After the covariates were controlled for, hypertensive subjects had higher peripheral resistance and lower arterial compliance than did normotensive participants, but cardiac output was not significantly different. Conclusion CFD is associated with more severe abnormalities in body composition and with higher CO independently of FFM in overweight, nonobese subjects.