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PurposeBirth weight (BW) is associated with risk of cardiovascular (CV) disease. The findings form studies examined the association of BW with metabolic markers of CV risk were inconsistent and controversial. We examined the association of BW with insulin resistance and blood lipids using repeated measures up to mid-adulthood.MethodsData from seven screenings of the Bogalusa Heart Study—a longitudinal study of cardiovascular risk factors in Bogalusa, LA, are analyzed using generalized estimation equations method. Participants with birth data and at least one measurement of study outcomes between 18-44 years of age (n=2,034) were included.ResultsBW is inversely associated with insulin resistance, triglycerides and total cholesterol (PConclusionsThe study provides strong evidence of an inverse relationship of BW with adulthood cardiometabolic risk profile. Persons born with low BW are maybe less responsive to preventive interventions aiming at weight reduction.

Background The clinical use of carotid intima media thickness (cIMT) requires normal values, which may be subject to variation of geographical factors, ethnicity or measurement details. The influence of these factors has rarely been studied. The aim of this study was to determine whether normative cIMT values and their association with event risk are generalizable across populations. Design Meta-analysis of individual participant data. Method From 22 general population cohorts from Europe, North America and Asia we selected subjects free of cardiovascular disease. Percentiles of cIMT and cIMT progression were assessed separately for every cohort. Cox proportional hazards models for vascular events were used to estimate hazard ratios for cIMT in each cohort. The estimates were pooled across Europe, North America and Asia, with random effects meta-analysis. The influence of geography, ethnicity and ultrasound protocols on cIMT values and on the hazard ratios was examined by meta-regression. Results Geographical factors, ethnicity and the ultrasound protocol had influence neither on the percentiles of cIMT and its progression, nor on the hazard ratios of cIMT for vascular events. Heterogeneity for percentiles of cIMT and cIMT progression was too large to create meaningful normative values. Conclusions The distribution of cIMT values is too heterogeneous to define universal or regional population reference values. CIMT values vary widely between different studies regardless of ethnicity, geographic location and ultrasound protocol. Prediction of vascular events with cIMT values was more consistent across all cohorts, ethnicities and regions.

AIMS: Carotid intima media thickness (CIMT) predicts cardiovascular (CVD) events, but the predictive value of CIMT change is debated. We assessed the relation between CIMT change and events in individuals at high cardiovascular risk. METHODS AND RESULTS: From 31 cohorts with two CIMT scans (total n = 89070) on average 3.6 years apart and clinical follow-up, subcohorts were drawn: (A) individuals with at least 3 cardiovascular risk factors without previous CVD events, (B) individuals with carotid plaques without previous CVD events, and (C) individuals with previous CVD events. Cox regression models were fit to estimate the hazard ratio (HR) of the combined endpoint (myocardial infarction, stroke or vascular death) per standard deviation (SD) of CIMT change, adjusted for CVD risk factors. These HRs were pooled across studies. In groups A, B and C we observed 3483, 2845 and 1165 endpoint events, respectively. Average common CIMT was 0.79mm (SD 0.16mm), and annual common CIMT change was 0.01mm (SD 0.07mm), both in group A. The pooled HR per SD of annual common CIMT change (0.02 to 0.43mm) was 0.99 (95% confidence interval: 0.95-1.02) in group A, 0.98 (0.93-1.04) in group B, and 0.95 (0.89-1.04) in group C. The HR per SD of common CIMT (average of the first and the second CIMT scan, 0.09 to 0.75mm) was 1.15 (1.07-1.23) in group A, 1.13 (1.05-1.22) in group B, and 1.12 (1.05-1.20) in group C. CONCLUSIONS: We confirm that common CIMT is associated with future CVD events in individuals at high risk. CIMT change does not relate to future event risk in high-risk individuals. The PROG-IMT project, which includes this publication, has been funded by the German Research Foundation (Deutsche Forschungsgemeinschaft, www.dfg.de) under the grants DFG Lo 1569/2-1 and DFG Lo 1569/2-3, received by MWL. The DFG had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Simon Thompson is supported by the British heart Foundation (CH/12/2/29428). Some of the contributing studies were funded by different parties, as listed in the acknowledgement section. Here, too, the funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Sí

The early onset of menarche is related to the adulthood risk of cardiovascular (CV) disease. This study examines the relation of early onset of menarche to carotid artery intima-media thickness (IMT), which is a surrogate marker of CV disease, among asymptomatic young adult women in a black-white community.A cohort of 461 women (31% black, 69% white) aged 24 to 43 years (mean of 35.6 years) were participants in the Bogalusa Heart Study. The age at menarche was retrospectively collected. In addition to CV risk factor variable measurements B-mode ultrasound images of the far walls of carotid artery segments were obtained. The multivariate linear regression model along with mediating effect by Sobel test was applied to analyze menarcheal age effect on carotid artery IMT, adjusting for covariates.Waist to height ratio was significantly greater (P = .01) in early menarcheal age (11 years) versus menarcheal age (≥11 years) in both black and white women. Homeostasis model assessment of insulin resistance (HOMA-IR) was significantly greater (P = .01) in early menarcheal age (11 years) versus menarcheal age (≥11 years) in white women and also similar direction in black women. Internal carotid artery IMT was the same in early menarcheal age (11 years) versus menarcheal age (≥11 years) in white women but higher (P = .02) in black women. Given as previously mentioned these different associations, the mediation analysis by race was performed. The effect of early menarcheal age (11 years) versus menarcheal age (≥11 years) was mediated by waist to height ratio and HOMA-IR in white women after adjusting for parental education and age. The mediating effect of waist to height ratio (Sobel test = -2.26 and P = .02) and HOMA-IR (Sobel test = -1.85 and P = .06) on internal carotid artery IMT was noted in white women. The direct effect of early menarcheal age (11 years) versus menarcheal age (≥11 years) on internal carotid artery IMT (β = -0.150, P = .01) was observed in black women.The observed deleterious effect of early onset of menarche on carotid artery IMT in asymptomatic black and white younger adult women has biological, social, and public health implications.

Secondhand smoke (SHS) exposure increases cardiovascular disease risk. The objective of this study was to examine the association of SHS exposure in childhood and adulthood with adult arterial thickness.The study cohort consisted of 415 nonsmoking adults (301 whites and 114 blacks; ages 26.2-48.0 years) enrolled in 2004-2010. The arterial wall thickness was measured as common, bulb and internal carotid artery intima-media thickness (IMT). SHS exposure data in childhood and adulthood were obtained by a questionnaire survey.Increased adult composite carotid IMT was significantly associated with SHS exposure (regression coefficient, β = 53.1 μm, p 0.001) after adjusting for race, age, gender, education, income, body mass index, systolic blood pressure, LDL cholesterol and triglycerides/HDL cholesterol ratio, with blacks (β = 81.2 μm, p = 0.005) and whites (β = 38.9 μm, p = 0.017) showing the same direction of the association. Furthermore, the SHS exposure in childhood showed a relatively stronger association with increased carotid IMT than the exposure in adulthood based on standardized βs (0.180 vs. 0.106); the same trend in the difference between childhood and adulthood exposure was noted for duration of SHS exposure (0.186 vs. 0.145). The covariates-adjusted composite carotid IMT showed a significant increasing trend by the order of exposure status of none, adulthood only, childhood only and both (p for trend0.001).If the relationship is causal, the associations observed in this study suggest that more awareness should be raised on the dangers of SHS exposure during childhood so that its effect may be mitigated and controlled early in the cardiovascular disease process.

Objectives To examine the associations of five GWAS-identified genes with carotid intima-media thickness (IMT) in a biracial sample from the Bogalusa Heart Study, and evaluate their participation in gene-smoking interactions. Methods Far wall IMTs of common carotid arteries were measured using high-resolution B-mode ultrasound. Both the gene-smoking interactions and single-marker associations were evaluated by linear models of carotid IMT levels, while the gene-based analyses were assessed through the truncated product method. A Bonferroni multiple testing correction was applied. Results Marker rs7840785 ( PINX1 ) was significantly associated with right carotid IMT (p = 0.0003) using all participants; mean levels for the CC, TC, and TT genotypes were 0.74 (0.73 to 0.75), 0.76 (0.75 to 0.78), and 0.78 (0.75, 0.81), respectively. Similar trends were observed in blacks (p = 0.0031) and whites (p = 0.0118). Marker rs7844465 ( ZHX2 ) was significantly associated with left carotid IMT in whites (p = 0.0005); mean IMT levels for the GG, TG, and TT genotypes were 0.73 (0.71 to 0.74), 0.75 (0.74 to 0.77) and 0.78 (0.75 to 0.81), respectively. Marker rs6841473 ( EDNRA ) modified the association between smoking and left carotid IMT in blacks (p = 2.79 × 10 − 5 ). In addition, gene-based analysis demonstrated that EDNRA and ZHX2 were associated with left carotid IMT in the white and overall participants, respectively, while PINX1 was associated with right carotid IMT in both blacks and whites. Conclusion We identified two novel markers that were associated with IMT in both blacks and whites. One gene-smoking interaction was identified in blacks only. Three genes showed gene-based associations with IMT levels. However, genetic markers with small effects may have been missed due to the limited number of black participants.

© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com. The electrocardiographic QRS duration, a measure of ventricular depolarization and conduction, is associated with cardiovascular mortality. While single nucleotide polymorphisms (SNPs) associated with QRS duration have been identified at 22 loci in populations of European descent, the genetic architecture of QRS duration in non-European populations is largely unknown. We therefore performed a genome-wide association study (GWAS) meta-analysis of QRS duration in 13,031 African Americans from ten cohorts and a transethnic GWAS meta-analysis with additional results from populations of European descent. In the African American GWAS, a single genome-wide significant SNP association was identified (rs3922844, P = 4 × 10-14) in intron 16 of SCN5A, a voltage-gated cardiac sodium channel gene. The QRS-prolonging rs3922844 C allele was also associated with decreased SCN5A RNA expression in human atrial tissue (P = 1.1 × 10-4). High density genotyping revealed that the SCN5A association region in African Americans was confined to intron 16. Transethnic GWAS meta-analysis identified novel SNP associations on chromosome 18 in MYL12A (rs1662342, P = 4.9 × 10-8) and chromosome 1 near CD1E and SPTA1 (rs7547997, P = 7.9 × 10-9). The 22 QRS loci previously identified in populations of European descent were enriched for significant SNP associations with QRS duration in African Americans (P = 9.9 × 10-7), and index SNP associations in or near SCN5A, SCN10A, CDKN1A, NFIA, HAND1, TBX5 and SETBP1 replicated in African Americans. In summary, rs3922844 was associated with QRS duration and SCN5A expression, two novel QRS loci were identified using transethnic meta-analysis, and a significant proportion of QRS-SNP associations discovered in populations of European descent were transferable to African Americans when adequate power was achieved.

Background More than 600 deaths of all causes have been documented over the 40-year duration of the Bogalusa Heart Study. Of these, 97 deaths have been related to cardiovascular events, based on obituaries published in local newspapers, death certificates obtained from the State Health Department, information from the coroner and word of mouth by nursing staff from the community. Methods This study was a retrospective longitudinal cohort with several observations of each subject. It consisted of 6 cross-sectional surveys of children aged 5-7 years, conducted between 1973 and 1988, and 4 cross-sectional surveys of previously examined subjects as young adults extending into middle age, conducted between 1988 and 2010. Results Excluding pulmonary, congenital and noncoronary cardiovascular diseases, 46 deaths (average age at death = 44.7 years, range: 31-55) were considered to have been related to coronary artery disease, that is, myocardial infarction. Cardiovascular risk factor observations, gathered from multiple surveys (average of 4.4 surveys, range: 1-14) since childhood, indicated that body fatness and elevated blood pressure beginning in childhood were more common in subjects who later died of coronary artery disease than in living subjects. Conclusions The present findings emphasize that sub-clinical cardiovascular disease begins early in life and that early prevention is vital.

Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering ∼2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids. © 2012 The American Society of Human Genetics.

Obesity, as a metabolic disorder, can be either a cause or consequence of epigenetic alterations, but their temporal relationship is unknown. This study assessed the hypothesis that BMI and DNA methylation changes mutually influence each other, dependent on different methylation sites in the human genome. Peripheral leukocyte DNA methylation data on 294,840 CpG sites filtered from 485,577 sites generated by Illumina 450K BeadChip were analyzed in two discovery cohorts (585 whites and 245 blacks) and a longitudinal cohort (95 whites and 43 blacks followed 3.2 years) in the Bogalusa Heart Study (BHS) and 2 replication cohorts (450 twins in Chinese National Twin Study, 456 blacks in Georgia Prevention Institute Epigenetics of Obesity Study). BMI was significantly associated with methylation levels at cg17260706 (negatively), cg13562284 (negatively) and cg15721584 (positively) consistently in the discovery cohorts, and these associations were replicated in both 450 Chinese twins and 456 blacks in the same directions. The temporal relationship analyses in a cross-lagged path analysis model showed a one-directional relation from BMI to methylation changes at cg17260706 in BCL9L gene in both races as seen in the figure. The temporal relationship was different in blacks versus whites for the other two CpGs. In longitudinal analysis of BMI measured 4 or more times over 40 years in the BHS, childhood (p

In this study, we conducted an epigenome-wide association study of metabolic syndrome (MetS) among 846 participants of European descent in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN). DNA was isolated from CD4+ T cells and methylation at ~470,000 cytosine-phosphate-guanine dinucleotide (CpG) pairs was assayed using the Illumina Infinium HumanMethylation450 BeadChip. We modeled the percentage methylation at individual CpGs as a function of MetS using linear mixed models. A Bonferroni-corrected P-value of 1.1 x 10(-7) was considered significant. Methylation at two CpG sites in CPT1A on chromosome 11 was significantly associated with MetS (P for cg00574958 = 2.6x10(-14) and P for cg17058475 = 1.2x10(-9)). Significant associations were replicated in both European and African ancestry participants of the Bogalusa Heart Study. Our findings suggest that methylation in CPT1A is a promising epigenetic marker for MetS risk which could become useful as a treatment target in the future.

systemic inflammation - as measured by high-sensitivity C-reactive protein (hs-CRP) - is adversely associated with arterial compliance. However, information is scant on whether this association in consistent throughout the different non-invasive measurements of arterial compliance. The purpose of