Background Genome-wide association studies have identified multiple variants associating with coronary artery disease (CAD) and myocardial infarction (MI). Whether a combined genetic risk score (GRS) is associated with prevalent and incident MI in high risk subjects remains to be established. Methods and Results In subjects undergoing cardiac catheterization (n=2597) we identified cases with a history of MI onset at age <70 years and controls ≥70 years old without prior MI, and followed them for incident MI and death. Genotyping was performed for 11 established CAD/MI variants and a GRS calculated based on average number of risk alleles carried at each locus weighted by effect size. Replication of association findings was sought in an independent angiographic cohort (n=2702). The GRS was significantly associated with prevalent MI, occurring before age 70 years, compared to older controls (≥70 years) with no history of MI (p<0.001). This association was successfully replicated in a second cohort yielding a pooled p value of <0.001. The GRS modestly improved the c-statistic in models of prevalent MI with traditional risk factors. However, the association was not statistically significant when elderly controls without MI but with stable angiographic CAD were examined (pooled p=0.11). Finally, during a median 2.5 year follow-up, only a non-significant trend was noted between the GRS and incident events, which was also not significant in the replication cohort. Conclusions A GRS of 11 CAD/MI variants is associated with prevalent MI but not near term incident adverse events in two independent angiographic cohorts. These findings have implications for understanding the clinical utility of genetic risk scores for secondary as opposed to primary risk prediction.

Background: Serum 25-hydroxyvitamin D [25(OH)D] concentrations can be affected by several environmental and individual factors. It is not clear to what extent genetic influences play a role in determining vitamin D status. Thus far, studies on the heritability of vitamin D have provided conflicting results. Objective: We estimated the heritability of vitamin D concentrations and the effect of season on heritability estimates. Design: We measured serum 25(OH)D concentrations in 510 middle-aged, male twins (310 monozygotic and 200 dizygotic twins) selected from the Vietnam Era Twin Registry. Generalized estimating equations were used to test the association between 25(OH)D and other study factors. Structural equation modeling was used to estimate the heritability of 25(OH)D. Results: The twins’ mean (±SD) age was 55 ± 2.8 y. The mean (±SD) 25(OH)D concentration was 38.4 ± 23.3 ng/mL with a substantial seasonal variation (a 6.1-ng/mL lower value during the winter than during the summer, P = 0.003). Approximately 70% of the variation in 25(OH)D concentrations during the winter was explained by genetic factors. However, in the summer, 25(OH)D concentrations were not heritable. During the summer, 53% of the variation in 25(OH)D concentrations was due to shared environmental factors, and 47% of the variation in 25(OH)D concentrations was due to unique environmental factors. Conclusions: Serum 25(OH)D concentrations are highly heritable during the winter season only. In the summer, environmental conditions (eg, sun exposure) prevail over genetic backgrounds in determining serum 25(OH)D concentrations. This trial was registered at clinicaltrials.gov as NCT00017836.

Aims We tested the hypothesis that the 9p21 risk locus promotes atherosclerosis by examining the association between rs10757278 and coronary artery disease (CAD) severity and progression determined by semi-quantitative angiographic scores. Methods and results The rs10757278 single nucleotide polymorphism (SNP) was genotyped as the marker for the 9p21 locus in 2334 Caucasian patients undergoing cardiac catheterization (mean age 63, male 67%). Angiographic CAD was assessed using two semi-quantitative scoring systems with one estimating severity (Gensini) and the other extent (Sullivan). A subset of 308 patients who underwent two or more coronary angiograms at least 6 months apart were examined for net change in Gensini and Sullivan scores over time to determine the rate of CAD progression by genotype and were further classified as ‘progressors’ or ‘non-progressors’ based on absolute change per year in angiographic severity score. We replicated the association between the rs10757278 SNP and myocardial infarction and binary (presence/absence) angiographic classifications of CAD. Furthermore, we observed a significant additive association with this SNP, and both severity and extent of CAD using angiographic scores, after adjustment for age, gender, body mass index, traditional cardiovascular risk factors, myocardial infarction, and statin use (Gensini P = 0.016, Sullivan P = 0.005). In addition, there was a significant linear association with CAD progression before and after adjustment for covariates (Gensini P = 0.023, Sullivan P = 0.003) with homozygotes for the risk variant having three-fold greater odds of CAD progression compared with the referent group. Conclusion The 9p21 risk locus is associated with angiographically defined severity, extent, and progression of CAD, suggesting a role for this locus in influencing atherosclerosis and its progression.

Background Despite evidence linking obesity to impaired immune function, little is known about the specific mechanisms. Because of emerging evidence that immune responses are epigenetically regulated, we hypothesized that DNA methylation changes are involved in obesity induced immune dysfunction and aimed to identify these changes. Method We conducted a genome wide methylation analysis on seven obese cases and seven lean controls aged 14 to 18 years from extreme ends of the obesity distribution and performed further validation of six CpG sites from six genes in 46 obese cases and 46 lean controls aged 14 to 30 years. Results In comparison with the lean controls, we observed one CpG site in the UBASH3A gene showing higher methylation levels and one CpG site in the TRIM3 gene showing lower methylation levels in the obese cases in both the genome wide step (P = 5 × 10-6 and P = 2 × 10-5 for the UBASH3A and the TRIM3 gene respectively) and the validation step (P = 0.008 and P = 0.001 for the UBASH3A and the TRIM3 gene respectively). Conclusions Our results provide evidence that obesity is associated with methylation changes in blood leukocyte DNA. Further studies are warranted to determine the causal direction of this relationship as well as whether such methylation changes can lead to immune dysfunction. See commentary: http://www.biomedcentral.com/1741-7015/8/88/abstract

Background: Our research group recently reported that aorto-radial (radial) and aorto-dorsalis-pedis (foot) pulse wave velocity (PWV) as proxies of arterial stiffness are substantially heritable in healthy youth. This article aimed at uncovering the genetic contributions of adhesion molecules, key members in the inflammatory process, to PWV in these young individuals. Methods: Radial and foot PWV were noninvasively measured with applanation tonometry in 702 black and white subjects (42% blacks, mean age 17.7 ± 3.3 years) from the Georgia Cardio vascular Twin Study. Eight functional polymorphisms from genes for E-selectin (SELE), P-selectin (SELP), intercellular adhesion molecules-1 (ICAM1), and vascular cell adhesion molecules-1 (VCAM1) were genotyped. Results: Youth with Ser290Asn or Asn290Asn genotype (SELP) compared to those with Ser290Ser had an increase in both radial and foot PWV (6.61 ± 0.07 vs. 6.41 ± 0.05 m/s, p= .026; 7.22 ± 0.05 vs. 7.04 ± 0.04 m/s, p = .007). TT homozygotes of rs2244529 (SELP) had higher foot PWV (7.28 ± 0.07 vs. 7.06 ± 0.03 m/s, p = .002) than CT heterozygotes and CC homozygotes. There appeared to be a decrease in foot PWV in youth with the 241Arg allele (ICAM1) as compared to those without (6.96 ± 0.08 vs. 7.14 ± 0.03 m/s, p= .005). For the Asp693Asp (C to T) polymorphism (VCAM1), CC genotype had higher foot PWV than CT and TT genotypes (7.18 ± 0.04 vs. 6.95 ± 0.06 m/s, p < .0001). There was an epistatic interaction between Ser290Asn, Gly241Arg, and Asp693Asp on foot PWV (p = .017), explaining 3.6% variance of the foot PWV. Conclusion: Genetic variation of adhesion molecules may be implicated in the development of arterial stiffness. Screening for adhesion molecule polymorphisms may help identify high-risk youth.

OBJECTIVE: To examine whether the genetic influences on blood pressure (BP) during night-time are different from those during daytime and the extent to which they depend on ethnicity or sex. METHODS: Ambulatory BP was measured in 240 Europeanĝ€"American and 190 Africanĝ€" American twins (mean ± SD age, 17.2 ± 3.4). Individuals with night-time BP falls more than 10% of the daytime values were defined as dippers. A bivariate analysis of the daytime and the night-time BP levels, as well as a liability-threshold model of dippers vs. nondippers were used. RESULTS: Bivariate model fitting showed no ethnic or sex differences for any of the measures, with heritabilities of 0.70 and 0.68 for SBP and 0.70 and 0.64 for DBP at daytime and at night-time. The genetic influences on daytime and night-time were not significantly different for SBP or DBP. The bivariate analysis also indicated that about 56 and 33% of the heritabilities of night-time SBP and DBP could be attributed to genes that also influenced daytime levels. The specific heritabilities due to genetic effects only influencing night-time values were 0.30 for SBP and 0.43 for DBP. The heritabilities of systolic and diastolic dipping were 0.59 and 0.81, respectively. CONCLUSION: Independent of ethnicity and sex, an overlap exists between genes that influence daytime and night-time BP, as well as a significant genetic component that is specific to the night-time BP. These findings suggest that different genes or sets of genes contribute to BP regulation at daytime and night-time.

We tested whether the heritability of heart rate variability (HRV) under stress is different from rest and its dependency on ethnicity or gender. HRV indexed by root mean square of successive differences (RMSSD) and high-frequency (HF) power was measured at rest and during 3 stressors in 427 European and 308 African American twins. No ethnic or gender differences were found for any measures. There was a nonsignificant increase in heritability of RMSSD (from 0.48 to 0.58) and HF (from 0.50 to 0.58) under stress. Up to 81% and 60% of the heritabilities of RMSSD and HF under stress could be attributed to genes influencing rest levels. The heritabilities due to genes expressed under stress were 0.11 for RMSSD and 0.23 for HF. The findings suggest that, independent of ethnicity and gender, HRV regulation at rest and under stress is largely influenced by the same genes with a small but significant contribution of stress-specific genetic effects. Copyright

Objectives High blood pressure variability is increasingly used as a predictor of target-organ damage and cardiovascular events. However, little is known about blood pressure variability changes with age and its possible sociodemographic, anthropometric, and genetic moderators. Methods Twenty-four-hour ambulatory blood pressure was measured up to 12 times over a 15-year period in 344 European Americans and 297 African-Americans with an average age of 14 years at the initial visit. Blood pressure variability was indexed by the weighted 24-h standard deviation of ambulatory blood pressure recordings. Results Both systolic and diastolic blood pressure variability increased with age and ambulatory blood pressure mean values. Men had higher levels of blood pressure variability (P<0.001) and showed steeper linear increase rates with age than women. African-Americans showed higher values of blood pressure variability (P<0.05) than European Americans. Body mass index and waist circumference were also associated with higher blood pressure variability levels (P<0.001). Individuals with higher father's education level showed lower blood pressure variability. In the full model which included all the above factors, ethnic difference in systolic blood pressure variability was no longer significant. Conclusion The results of the present study suggest that men and African-Americans have higher blood pressure variability than women and European Americans. Apart from these ethnicity and sex effects, blood pressure variability increases with increases in age (especially in men), ambulatory blood pressure mean values and adiposity as well as decreased socioeconomic status.

Background Genome-wide association studies (GWAS) have identified novel variants associated with myocardial infarction (MI) in Caucasians. We hypothesized that those variants whose mechanism of risk is currently unknown, confer risk via pathways mediating arterial wave reflections which is an increasingly recognized risk factor for cardiovascular disease. Methods Single-nucleotide polymorphisms (SNPs) at eight MI risk loci were genotyped and correlated with noninvasively determined pulse wave analysis (PWA)-derived central hemodynamic indexes (augmentation index (AIx); augmented pressure (AP); time to reflected wave (TrW) and central systolic blood pressure (SBP) and diastolic BP (DBP)) in two independent Caucasian populations including (i) those free of measured cardiovascular risk factors (n = 133) and (ii) a community-based population (n = 270). Results Of the eight SNPs examined in the healthy group, the variants at loci 6p24 (AIx and AP both P < 0.001, TrW P = 0.02) and 21q22 (AIx P = 0.002, TrW P = 0.037) were significantly associated with PWA indexes. In the replication group, only the 6p24 variant correlated with these phenotypes (AIx P = 0.005, AP P = 0.049, TrW P = 0.013). In the pooled population (n = 403), no new associations were identified but the association with 6p24 and AIx remained significant even after Bonferroni correction and adjustment for covariates including age, mean arterial pressure, height, gender, glucose, cholesterol, body mass index (BMI), and smoking (AIx (P = 0.03)). Each copy of the risk allele C increased the AIx by 3.5%. Conclusions The GWAS discovered MI risk variant at 6p24 in the protein phosphatase 1 regulator gene (PHACTR1) is associated with adverse arterial wave reflection indexes and may mediate MI risk through this pathway.

To determine to what extent the genetic influences on blood pressure (BP) measured in the office, under psychologically stressful conditions in the laboratory and during real life are different from each other. Office BP, BP during a video game challenge and a social stressor interview, and 24-h ambulatory BP were measured in 238 European American and 186 African American twins. BP values across the two tasks were averaged to represent stress levels. Genetic model fitting showed no ethnic or gender differences for any of the measures. The model fitting resulted in heritability estimates of 63, 75 and 71% for office, stress and 24-h systolic BP (SBP) and 59, 67 and 69% for diastolic BP (DBP), respectively. Up to 81% of the heritability of office SBP and 71% of office DBP were attributed to genes that also influenced stress BP. However, only 45% of the heritability of 24-h SBP and 49% of 24-h DBP were attributed to genes that also influence office BP. Similarly, about 39% of the heritability of 24-h SBP and 42% of 24-h DBP were attributed to genes that also influence stress BP. Substantial overlap exists between genes that influence BP measured in the office, under laboratory stress and during real life. However, significant genetic components specific to each BP measurement also exist. These findings suggest that partly different genes or sets of genes contribute to BP regulation in different conditions.