Correction: Predictive value for cardiovascular events of common carotid intima media thickness and its rate of change in individuals at high cardiovascular risk - Results from the PROG-IMT collaboration.

[This corrects the article DOI: 10.1371/journal.pone.0191172.].

Predictive value for cardiovascular events of common carotid intima media thickness and its rate of change in individuals at high cardiovascular risk - Results from the PROG-IMT collaboration.

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.

Adiposity and Cardiovascular Risk Factor Variables in Childhood Are Associated With Premature Death From Coronary Heart Disease in Adults: The Bogalusa Heart Study.

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.

Fine-mapping, novel loci identification, and SNP association transferability in a genome-wide association study of QRS duration in African Americans.

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.

Normative values for carotid intima media thickness and its progression: Are they transferrable outside of their cohort of origin?

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.

Association of DNA Methylation at CPT1A Locus with Metabolic Syndrome in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study.

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.

Secondhand smoke exposure is associated with increased carotid artery intima-media thickness: the Bogalusa Heart Study.

BACKGROUND: 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. METHODS: 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. RESULTS: Increased adult composite carotid IMT was significantly associated with SHS exposure (regression coefficient, ß = 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 (ß = 81.2 µm, p = 0.005) and whites (ß = 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 ßs (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 trend<0.001). CONCLUSIONS: 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.

Timing of menarche related to carotid artery intima-media thickness in black and white young adult women: the Bogalusa Heart Study.

PURPOSE: 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. METHODS: 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. RESULTS: 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 (ß = -0.150, P = .01) was observed in black women. CONCLUSIONS: 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.

Genetic association and gene-smoking interaction study of carotid intima-media thickness at five GWAS-indicated genes: the Bogalusa Heart Study.

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.

Tobacco smoking strengthens the association of elevated blood pressure with arterial stiffness: the Bogalusa Heart Study.

OBJECTIVES: The study assessed the hypothesis that smoking strengthens the association of adult arterial stiffness with long-term cumulative burden of blood pressure (BP) from childhood to adulthood. BACKGROUNDS: Tobacco smoking and elevated BPs are important risk factors of vascular stiffness. However, the synergistic effect of these two risk factors is not well established, especially for the long-term burden of elevated BP since childhood. METHODS: The study cohort consisted of 945 adults (661 whites and 284 blacks, aged 24-43 years) who have BP measured 4-15 times since childhood (aged 4-17 years) in Bogalusa, Louisiana. The adult arterial stiffness was measured as aorta-femoral pulse wave velocity (afPWV); the total area under the curve (AUC) and incremental AUC were used as a measure of long-term burden and trends of BP, respectively. RESULTS: Increased adult afPWV was significantly associated with higher adulthood (P < 0.001), total AUC (P < 0.001) and incremental AUC (P < 0.001) values of SBP and DBP, but not with childhood BP, after adjusting for age, race, sex, BMI and heart rate. Furthermore, smoking was a significant predictor of increased adult afPWV and BP levels. In the interaction analyses, the increasing trend of afPWV with increasing adult SBP (P = 0.009) and its incremental AUC (P = 0.007) were significantly greater among the current smokers than among the nonsmokers. DBP showed a similar pattern regarding the smoking-BP interaction on afPWV. CONCLUSION: These results, by showing the synergistic effect of tobacco smoking and long-term BP measures from childhood to adulthood on arterial stiffening process, underscore the importance of undertaking preventive strategies early in life and smoking behavior control.

Impact of long-term burden of excessive adiposity and elevated blood pressure from childhood on adulthood left ventricular remodeling patterns: the Bogalusa Heart Study.

BACKGROUND: Cardiovascular risk factors are associated with left ventricular hypertrophy (LVH), but little is known regarding related impact of longitudinal measures of childhood adiposity and LV hemodynamic variables. OBJECTIVES: The aim of this study was to examine the impact of cumulative long-term burden and trends of excessive adiposity and elevated blood pressure (BP) during childhood on adulthood LVH and LV geometric remodeling patterns. METHODS: This longitudinal study consisted of 1,061 adults, age 24 to 46 years, who had been examined 4 or more times for body mass index (BMI) and BP starting in childhood, with a mean follow-up of 28.0 years. The area under the curve (AUC) was calculated as a measure of long-term burden (total AUC) and trends (incremental AUC) of BMI and BP from childhood to adulthood. Four LV geometric types were defined-normal, concentric remodeling (CR), eccentric hypertrophy (EH), and concentric hypertrophy (CH)-all on the basis of LV mass indexed for body height (m(2.7)) and relative wall thickness. RESULTS: Higher values of BMI and systolic and diastolic BP in childhood and adulthood, as well as total AUC and incremental AUC, were all significantly associated with higher LV mass index and LVH, adjusted for race, sex, and age. In addition, higher values of BMI and BP in childhood and adulthood, total AUC, and incremental AUC were significantly associated with EH and CH but not with CR. Importantly, all of these measures of BMI had a consistently and significantly greater influence on EH than did measures of BP. CONCLUSIONS: These findings indicate that the adverse influence of excessive adiposity and elevated BP levels on LVH begins in childhood.

Uric acid is associated with metabolic syndrome in children and adults in a community: the Bogalusa Heart Study.

BACKGROUND: Elevated serum uric acid (UA) is commonly found in subjects with metabolic syndrome (MetS). This study examined the association of UA with levels of individual MetS components and the degree of their clustering patterns in both children and adults. METHODS: The study sample consisted of 2614 children aged 4-18 years and 2447 adults aged 19-54 years. MetS components included body mass index (BMI), mean arterial pressure (MAP), triglycerides to high-density lipoprotein cholesterol ratio (TG/HDLC), and homeostasis model assessment of insulin resistance (HOMA). Observed/expected (O/E) ratio and intra-class correlation coefficient (ICC) were used as a measure of the degree of clustering of categorical and continuous MetS variables, respectively. RESULTS: UA was positively and significantly associated only with BMI in children but with all four components in adults. The odds ratio for MetS associated with 1 mg/dL increase of UA was 1.74 (p<0.001) in children and 1.92 (p<0.001) in adults. O/E ratios showed a significant, increasing trend with increasing UA quartiles in both children and adults for 3- and 4-variable clusters with p-values for trend <0.001, except for BMI-MAP-TG/HDLC and MAP-TG/HDLC-HOMA clusters in children and MAP-TG/HDLC-HOMA cluster in adults. ICCs of 3 and 4 components increased with increasing UA quartiles in children and adults. CONCLUSIONS: These results indicate that UA may play a role in the development of MetS in both pediatric and adult populations alike, which may aid in the identification and treatment of high risk individuals for MetS and related clinical disorders in early life.

Cigarette smoking exacerbates the adverse effects of age and metabolic syndrome on subclinical atherosclerosis: the Bogalusa Heart Study.

Age and metabolic syndrome are major risk factors for atherosclerosis. However, limited information is available regarding whether cigarette smoking, another major, modifiable risk factor, has synergistic effects with age and metabolic syndrome on subclinical atherosclerosis, particularly in young adults. This aspect was examined in 1,051 adults (747 whites and 304 blacks; aged 24-43 years) from the Bogalusa Heart Study. General linear models were used to examine the effects of cigarette smoking and its interactive effects with age and metabolic syndrome on carotid intima-media thickness (CIMT). After adjusting for age, race, and sex, current smokers had lower BMI (mean ± SE: 27.4 ± 0.4, 29.3 ± 0.5, and 29.9 ± 0.3 kg/m2 in current, former, and never smokers, respectively; p<0.0001) and lower levels of fasting glucose (82.8 ± 0.9, 89.5 ± 2.3, and 87.1 ± 1.1 mg/dL, respectively; p = 0.001) and insulin (10.6 ± 0.4, 14.2 ± 1.0, 13.6 ± 0. 6 µU/ml, respectively; p<0.0001). Despite being lean and having favorable levels of glucose and insulin, current smokers had greater CIMT (0.850 ± 0.012, 0.808 ± 0.011, and 0.801 ± 0.006 mm, respectively; p = 0.0004). Importantly, cigarette smoking showed significant interactions with age and metabolic syndrome on CIMT: Age-related change in CIMT in current smokers was significantly greater (0.013 ± 0.002 mm/year) than in nonsmokers (former and never smokers combined) (0.008 ± 0.001 mm/year) (p for interaction = 0.005); the difference in CIMT between those with and without metabolic syndrome was significantly greater in current smokers (0.154 ± 0.030 mm, p<0.0001) than in nonsmokers (0.031 ± 0.014 mm, p = 0.03) (p for interaction<0.0001). In conclusion, cigarette smoking significantly exacerbates the adverse effects of age and metabolic syndrome on subclinical atherosclerosis in young adults, which underscores the importance of prevention and cessation of cigarette smoking behavior in the young.

Sex and race (black-white) differences in the relationship of childhood risk factors to adulthood arterial stiffness: the Bogalusa Heart Study.

BACKGROUND: Cardiovascular risk factors in childhood are predictive of adulthood arterial stiffness. However, it is unknown whether this relationship varies by race or sex. METHODS: Six hundred and eighty adults aged 24 to 43 had been followed for an average of 26.3 years, from the Bogalusa Heart Study. Brachial to ankle pulse wave velocity (baPWV) measured by an automatic oscillometric technique was used as the outcome variable for arterial stiffness during adulthood. Body mass index (BMI), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), glucose, and systolic blood pressure (SBP), all measured in childhood, were used as predictors. The average values of childhood measurements at multiple time points were used, standardized to age, race, and sex-specific z-scores. RESULTS: In the total sample, childhood SBP was the only significant predictor (P < 0.001) for adult baPWV. Significant interactions between sex and BMI (P = 0.001), between sex and LDL-C (P = 0.035), and between race and HDL-C (P = 0.002) on adult baPWV were identified. Childhood predictors of adult baPWV were BMI (30.9 cm/s reduction in baPWV per standard deviation increase, 95% confidence interval [CI]: -55.0, -6.9 cm/s), LDL-C (30.8 cm/s increase, 95% CI: 2.9, 59.5 cm/s), and HDL-C (46.8 cm/s reduction, 95% CI: -76.2, -17.4 cm/s) in white males; SBP (38.2 cm/s increase, 95% CI: 11.0, 65.4 cm/s) in white females; BMI (71.3 cm/s reduction, 95% CI: -119.9, -22.7 cm/s) in black males; and none in black females. CONCLUSIONS: The associations of childhood cardiovascular risk factors with adult arterial stiffness varied by race and sex.

Combined effects of child and adult elevated blood pressure on subclinical atherosclerosis: the International Childhood Cardiovascular Cohort Consortium.

BACKGROUND: Elevated blood pressure (BP) levels in childhood have been associated with subsequent atherosclerosis. However, it is uncertain whether this risk is attenuated in individuals who acquire normal BP by adulthood. The present study examined the effect of child and adult BP levels on carotid artery intima-media thickness (IMT) in adulthood. METHODS AND RESULTS: The cohort consisted of 4210 participants from 4 prospective studies (mean follow-up, 23 years). Childhood elevated BP was defined according to the tables from the National High Blood Pressure Education Program. In adulthood, BP was classified as elevated for individuals with systolic BP ≥120 mm Hg, diastolic BP ≥80 mm Hg or with self-reported use of antihypertensive medications. Carotid artery IMT was measured in the left common carotid artery. High IMT was defined as an IMT ≥90th percentile according to age-, sex-, race-, and cohort-specific levels. Individuals with persistently elevated BP and individuals with normal childhood BP, but elevated adult BP had increased risk of high carotid artery IMT (relative risk [95% confidence interval]) 1.82[1.47-2.38] and 1.57[1.22-2.02], respectively) in comparison with individuals with normal child and adult BP. In contrast, individuals with elevated BP as children but not as adults did not have significantly increased risk (1.24[0.92-1.67]). In addition, these individuals had a lower risk of increased carotid artery IMT (0.66[0.50-0.88]) in compared with those with persistently elevated BP. The results were consistent when controlling for age, sex, and adiposity and when different BP definitions were applied. CONCLUSIONS: Individuals with persistently elevated BP from childhood to adulthood had increased risk of carotid atherosclerosis. This risk was reduced if elevated BP during childhood resolved by adulthood.

Ideal cardiovascular health in young adult populations from the United States, Finland, and Australia and its association with cIMT: the International Childhood Cardiovascular Cohort Consortium.

BACKGROUND: Goals for cardiovascular (CV) disease prevention were set by the American Heart Association in 2010 for the concept of CV health. Ideal CV health is defined by 7 CV health metrics: blood pressure, glucose, cholesterol, body mass index, and physical activity on recommended levels; nonsmoking; and a healthy diet. We studied the prevalence of ideal CV health and its associations with ultrasonographically measured carotid intima-media thickness (cIMT) cross-sectionally in 5 international populations. METHODS AND RESULTS: Prevalence of ideal CV health was assessed among 5785 young adults (age, 36.6 ± 3.2 years) comprising 335 participants from the Minneapolis Childhood Cohort Studies (Minnesota), 723 from the Princeton Follow-up Study, 981 from the Bogalusa Heart Study (BHS), 1898 from the Cardiovascular Risk in Young Finns Study (YFS), and 1848 from the Childhood Determinants of Adult Health Study (CDAH). Only 1% of the participants had all 7 ideal CV health metrics. The number of ideal CV health metrics associated inversely with cIMT in the 4 cohorts in which cIMT was available: for each additional ideal CV health metric, cIMT was 12.7 µm thinner in Minnesota (P=0.0002), 9.1 µm thinner in BHS (P=0.05), 10.4 µm thinner in YFS (P<0.0001), and 3.4 µm thinner in CDAH (P=0.03). CONCLUSIONS: The number of ideal CV health metrics was inversely associated with cIMT in the cohorts in which cIMT was available, indicating that ideal CV health metrics are associated with vascular health at the population level. Ideal CV health was rare in this large international sample of young adults, emphasizing the need for effective strategies for health promotion.

Genomic risk models improve prediction of longitudinal lipid levels in children and young adults.

In clinical medicine, lipids are commonly measured biomarkers used to assess an individual's risk for cardiovascular disease, heart attack, and stroke. Accurately predicting longitudinal lipid levels based on genomic information can inform therapeutic practices and decrease cardiovascular risk by identifying high-risk patients prior to onset. Using genotyped and imputed genetic data from 523 unrelated Caucasian Americans from the Bogalusa Heart Study, surveyed on 4,026 occasions from 4 to 48 years of age, we generated various lipid genomic risk models based on previously reported markers. We observed a significant improvement in prediction over non-genetic risk models in high density lipoprotein cholesterol (increase in the squared correlation between observed and predicted values, ΔR (2) = 0.032), low density lipoprotein cholesterol (ΔR (2) = 0.053), total cholesterol (ΔR (2) = 0.043), and triglycerides (ΔR (2) = 0.031). Many of our approaches are based on an n-fold cross-validation procedure that are, by design, adaptable to a clinical environment.

Tracking and fixed ranking of leukocyte telomere length across the adult life course.

Short leukocyte telomere length (LTL) is associated with atherosclerosis in adults and diminished survival in the elderly. LTL dynamics are defined by LTL at birth, which is highly variable, and its age-dependent attrition thereafter, which is rapid during the first 20 years of life. We examined whether age-dependent LTL attrition during adulthood can substantially affect individuals' LTL ranking (e.g., longer or shorter LTL) in relation to their peers. We measured LTL in samples donated 12 years apart on average by 1156 participants in four longitudinal studies. We observed correlations of 0.91-0.96 between baseline and follow-up LTLs. Ranking individuals by deciles revealed that 94.1% (95% confidence interval of 92.6-95.4%) showed no rank change or a 1 decile change over time. We conclude that in adults, LTL is virtually anchored to a given rank with the passage of time. Accordingly, the links of LTL with atherosclerosis and longevity appear to be established early in life. It is unlikely that lifestyle and its modification during adulthood exert a major impact on LTL ranking.

Genome-wide association study of age at menarche in African-American women.

African-American (AA) women have earlier menarche on average than women of European ancestry (EA), and earlier menarche is a risk factor for obesity and type 2 diabetes among other chronic diseases. Identification of common genetic variants associated with age at menarche has a potential value in pointing to the genetic pathways underlying chronic disease risk, yet comprehensive genome-wide studies of age at menarche are lacking for AA women. In this study, we tested the genome-wide association of self-reported age at menarche with common single-nucleotide polymorphisms (SNPs) in a total of 18 089 AA women in 15 studies using an additive genetic linear regression model, adjusting for year of birth and population stratification, followed by inverse-variance weighted meta-analysis (Stage 1). Top meta-analysis results were then tested in an independent sample of 2850 women (Stage 2). First, while no SNP passed the pre-specified P < 5 × 10(-8) threshold for significance in Stage 1, suggestive associations were found for variants near FLRT2 and PIK3R1, and conditional analysis identified two independent SNPs (rs339978 and rs980000) in or near RORA, strengthening the support for this suggestive locus identified in EA women. Secondly, an investigation of SNPs in 42 previously identified menarche loci in EA women demonstrated that 25 (60%) of them contained variants significantly associated with menarche in AA women. The findings provide the first evidence of cross-ethnic generalization of menarche loci identified to date, and suggest a number of novel biological links to menarche timing in AA women.