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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, d=0.032), low density lipoprotein cholesterol (d=0.053), total cholesterol (d=0.043), and triglycerides (d=0.031). Many of our approaches are based on an n-fold cross-validation procedure that are, by design, adaptable to a clinical environment.

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

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.

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.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.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

Leukocyte telomere length (LTL) is ostensibly a biomarker of human aging. Cross-sectional analyses have found that LTL is relatively short in a host of aging-related diseases. These studies have also provided indirect estimates of age-dependent LTL shortening. In this paper, the authors report findings of the first comprehensive longitudinal study of 450 whites and 185 African Americans in Louisiana (aged 31.4 and 37.4 years at baseline (1995–1996) and follow-up (2001–2006) examinations, respectively) participating in the Bogalusa Heart Study. Rate of change in LTL was highly variable among individuals, with some displaying a paradoxical gain in LTL during the follow-up period. The most striking observation was that age-dependent LTL shortening was proportional to LTL at baseline examination. At both baseline and follow-up examinations, African Americans had longer LTLs than whites, and smokers had shorter LTLs than nonsmokers. The longer LTL in African Americans than in whites explained in part the faster rate of LTL shortening observed among African Americans. These findings underscore the complexity of leukocyte telomere dynamics in vivo and suggest that determinants in addition to the “end-replication problem” contribute to telomere shortening in vivo. [ABSTRACT FROM AUTHOR]

The effect of birth weight on white blood cell (WBC) count among blacks and whites was examined in 2,080 children (aged 4–11 years, 57.4% white, and 49.2% male), 892 adolescents (aged 12–17 years, 57.2% white, and 50.8% male), and 1,872 adults (aged 18–38 years, 68.4% white, and 41.9% male) from Bogalusa, Louisiana, in 2005. After adjustment for age, sex, race, body mass index, and smoking status (in adolescents and adults), the WBC count decreased across quartiles of increasing birth weight specific for race, sex, and gestational age in children (Ptrend = 0.0007) and adults (Ptrend = 0.005). In multivariate regression analyses that included the covariates above, birth weight was inversely associated with WBC count in children (β coefficients (unit, cells/μL per kg) = −256, −241, and −251 for whites, blacks, and the combined sample, with P = 0.003, 0.029, and <0.001, respectively) and in adults (β = −224 and −211 for whites and the combined sample, with P = 0.015 and 0.008, respectively). These results show that low birth weight is associated with increased systemic inflammation as depicted by the WBC count in childhood and adulthood, thereby potentially linking fetal growth retardation to cardiovascular disease and diabetes. [ABSTRACT FROM AUTHOR]

Clustering of long-term rates of change in metabolic syndrome variables (body mass index, homeostasis model assessment of insulin resistance, ratio of triglycerides to high-density lipoprotein cholesterol, and mean arterial pressure) from childhood to adulthood was evaluated longitudinally (1982–2003) in a cohort of 389 Blacks and 631 Whites who were examined 3–6 times both as children (ages 4–17 years) and as adults (ages 18–38 years) over an average of 16 years (3,874 observations). The incremental area under the growth curve was used as a measure of long-term rates of change in risk variables since childhood. Intraclass correlations, a measure of the degree of clustering, among the four variables were significant (p < 0.001) for childhood, adulthood, and incremental area values and were higher in adulthood than in childhood. Blacks showed a higher degree of clustering of long-term rates of change in risk variables than did Whites. Adjustment for body mass index reduced the degree of clustering by approximately 50%. These results show that metabolic syndrome variables coexist in terms not only of their levels in childhood and adulthood but also of long-term rates of change. Obesity is of critical importance in the development of metabolic syndrome, and its prevention beginning in childhood needs to be addressed. [ABSTRACT FROM AUTHOR]

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.

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

Genome-wide association studies (GWASs) have identified a large number of variants (SNPs) associating with an increased risk of coronary artery disease (CAD). Recently, the CARDIoGRAM consortium published a GWAS based on the largest study population so far. They successfully replicated twelve already known associations and discovered thirteen new SNPs associating with CAD. We examined whether the genetic profiling of these variants improves prediction of subclinical atherosclerosis--i.e., carotid intima-media thickness (CIMT) and carotid artery elasticity (CAE)--beyond classical risk factors.We genotyped 24 variants found in a population of European ancestry and measured CIMT and CAE in 2001 and 2007 from 2,081, and 2,015 subjects (aged 30-45 years in 2007) respectively, participating in the Cardiovascular Risk in Young Finns Study (YFS). The Bogalusa Heart Study (BHS; n = 1179) was used as a replication cohort (mean age of 37.5). For additional replication, a sub-sample of 5 SNPs was genotyped for 1,291 individuals aged 46-76 years participating in the Health 2000 population survey. We tested the impact of genetic risk score (GRS(24SNP/CAD)) calculated as a weighted (by allelic odds ratios for CAD) sum of CAD risk alleles from the studied 24 variants on CIMT, CAE, the incidence of carotid atherosclerosis and the progression of CIMT and CAE during a 6-year follow-up.CIMT or CAE did not significantly associate with GRS(24SNP/CAD) before or after adjusting for classical CAD risk factors (p>0.05 for all) in YFS or in the BHS. CIMT and CAE associated with only one SNP each in the YFS. The findings were not replicated in the replication cohorts. In the meta-analysis CIMT or CAE did not associate with any of the SNPs.Genetic profiling, by using known CAD risk variants, should not improve risk stratification for subclinical atherosclerosis beyond conventional risk factors among healthy young adults.

Cardiovascular disease (CVD) is the leading cause of death worldwide. Recent genome-wide association (GWA) studies have pinpointed many loci associated with CVD risk factors in adults. It is unclear, however, if these loci predict trait levels at all ages, if they are associated with how a trait develops over time, or if they could be used to screen individuals who are pre-symptomatic to provide the opportunity for preventive measures before disease onset. We completed a genome-wide association study on participants in the longitudinal Bogalusa Heart Study (BHS) and have characterized the association between genetic factors and the development of CVD risk factors from childhood to adulthood. We report 7 genome-wide significant associations involving CVD risk factors, two of which have been previously reported. Top regions were tested for replication in the Young Finns Study (YF) and two associations strongly replicated: rs247616 in CETP with HDL levels (combined P = 9.7 x 10(-24)), and rs445925 at APOE with LDL levels (combined P = 8.7 x 10(-19)). We show that SNPs previously identified in adult cross-sectional studies tend to show age-independent effects in the BHS with effect sizes consistent with previous reports. Previously identified variants were associated with adult trait levels above and beyond those seen in childhood; however, variants with time-dependent effects were also promising predictors. This is the first GWA study to evaluate the role of common genetic variants in the development of CVD risk factors in children as they advance through adulthood and highlights the utility of using longitudinal studies to identify genetic predictors of adult traits in children.