Concept, design and implementation of a cardiovascular gene-centric 50 k SNP array for large-scale genomic association studies.

A wealth of genetic associations for cardiovascular and metabolic phenotypes in humans has been accumulating over the last decade, in particular a large number of loci derived from recent genome wide association studies (GWAS). True complex disease-associated loci often exert modest effects, so their delineation currently requires integration of diverse phenotypic data from large studies to ensure robust meta-analyses. We have designed a gene-centric 50 K single nucleotide polymorphism (SNP) array to assess potentially relevant loci across a range of cardiovascular, metabolic and inflammatory syndromes. The array utilizes a "cosmopolitan" tagging approach to capture the genetic diversity across approximately 2,000 loci in populations represented in the HapMap and SeattleSNPs projects. The array content is informed by GWAS of vascular and inflammatory disease, expression quantitative trait loci implicated in atherosclerosis, pathway based approaches and comprehensive literature searching. The custom flexibility of the array platform facilitated interrogation of loci at differing stringencies, according to a gene prioritization strategy that allows saturation of high priority loci with a greater density of markers than the existing GWAS tools, particularly in African HapMap samples. We also demonstrate that the IBC array can be used to complement GWAS, increasing coverage in high priority CVD-related loci across all major HapMap populations. DNA from over 200,000 extensively phenotyped individuals will be genotyped with this array with a significant portion of the generated data being released into the academic domain facilitating in silico replication attempts, analyses of rare variants and cross-cohort meta-analyses in diverse populations. These datasets will also facilitate more robust secondary analyses, such as explorations with alternative genetic models, epistasis and gene-environment interactions.

Double-blind comparison of rectally administered diazepam to placebo for pediatric sedation: the cardiovascular response.

The sedative and cardiovascular effects of rectally administered diazepam (0.6 mg/kg) were compared to placebo in uncooperative children who required sedation during dental treatment. Twelve healthy preschool children, who required amalgam restorations, were treated during two standardized restorative appointments in a double-blind, crossover study. Blood pressure and pulse were obtained during four specified intervals during the appointment. The behavior of the children during the treatment visits was videotaped and later statistically analyzed using a kinesics/vocalization instrument. Behavioral ratings of cooperation were significantly improved during the treatment visit following diazepam. All interfering bodily movements, patient vocalizations and operator commands for the diazepam group were reduced significantly (p≤0.0001). No significant differences were observed for noninterfering behavioral response. Rectally administered diazepam did not alter blood pressure or pulse significantly in these sedated children when compared to the placebo. These findings indicate that rectal diazepam is an effective sedative agent with minimal effect on the cardiovascular system for the management of the young pediatric dental patient.

A study of the relationship between physical activity and cardiovascular fitness and coronary heart disease risk factors in female adolescents

The association of measures of physical activity with coronary heart disease (CHD) risk factors in children, especially those for atherosclerosis, is unknown. The purpose of this study was to determine the association of physical activity and cardiovascular fitness with blood lipids and lipoproteins in pre-adolescent and adolescent girls.^ The study population was comprised of 131 girls aged 9 to 16 years who participated in the Children's Nutrition Research Center's Adolescent Study. The dependent variables, blood lipids and lipoproteins, were measured by standard techniques. The independent variables were physical activity measured as the difference between total energy expenditure (TEE) and basal metabolic rate (BMR), and cardiovascular fitness, VO$\rm\sb{2max}$(ml/min/kg). TEE was measured by the doubly-labeled water (DLW) method, and BMR by whole-room calorimetry. Cardiovascular fitness, VO$\rm\sb{2max}$(ml/min/kg), was measured on a motorized treadmill. The potential confounding variables were sexual maturation (Tanner breast stage), ethnic group, body fat percent, and dietary variables. A systematic strategy for data analysis was used to isolate the effects of physical activity and cardiovascular fitness on blood lipids, beginning with assessment of confounding and interaction. Next, from regression models predicting each blood lipid and controlling for covariables, hypotheses were evaluated by the direction and value of the coefficients for physical activity and cardiovascular fitness.^ The main result was that cardiovascular fitness appeared to be more strongly associated with blood lipids than physical activity. An interaction between cardiovascular fitness and sexual maturation indicated that the effect of cardiovascular fitness on most blood lipids was dependent on the stage of sexual maturation.^ A difference of 760 kcal/d physical activity (which represents the difference between the 25th and 75th percentile of physical activity) was associated with negligible differences in blood lipids. In contrast, a difference in 10 ml/min/kg of VO$\rm\sb{2max}$ or cardiovascular fitness (which represents the difference between the 25th and 75th percentile in cardiovascular fitness) in the early stages of sexual maturation was associated with an average positive difference of 15 mg/100 ml ApoA-1 and 10 mg/100 ml HDL-C. ^

Prediction of cardiovascular disease risk factors in Mexican-American children from parental risk factors, and social and demographic characteristics in the HHANES

Objectives. Cardiovascular disease (CVD) including CVD secondary to diabetes type II, a significant health problem among Mexican American populations, originates in early childhood. This study seeks to determine risk factors available to the health practitioner that can identify the child at potential risk of developing CVD, thereby enabling early intervention. ^ Design. This is a secondary analysis of cross-sectional data of matched Mexican American parents and children selected from the HHANES, 1982–1984. ^ Methods. Parents at high risk for CVD were identified based on medical history, and clinical and physical findings. Factor analysis was performed on children's skinfold thicknesses, height, weight, and systolic and diastolic blood pressures, in order to produce a limited number of uncorrelated child CVD risk factors. Multiple regression analyses were then performed to determine other CVD markers associated with these Factors, independently for mothers and fathers. ^ Results. Factor analysis of children's measurements revealed three uncorrelated latent variables summarizing the children's CVD risk: Factor1: ‘Fatness’, Factor2: ‘Size and Maturity’, and Factor3: ‘Blood Pressure’, together accounting for the bulk of variation in children's measurements (86–89%). Univariate analyses showed that children from high CVD risk families did not differ from children of low risk families in occurrence of high blood pressure, overweight, biological maturity, acculturation score, or social and economic indicators. However, multiple regression using the factor scores (from factor analysis) as dependent variables, revealed that higher CVD risk in parents, was significantly associated with increased fatness and increased blood pressure in the children. Father's CVD risk status was associated with higher levels of body fat in his children and higher levels of blood pressure in sons. Mother's CVD risk status was associated with higher blood pressure levels in children, and occurrence of obesity in the mother associated with higher fatness levels in her children. ^ Conclusion. Occurrence of cardiovascular disease and its risk factors in parents of Mexican American children, may be used to identify children at potentially higher risk for developing CV disease in the future. Obesity in mothers appears to be an important marker for the development of higher levels of body fatness in children. ^

A longitudinal comparison of cardiovascular disease risk factors among children and adolescents in the U.S. and Japan: Project HeartBeat!

Blood cholesterol and blood pressure development in childhood and adolescence have important impact on the future adult level of cholesterol and blood pressure, and on increased risk of cardiovascular diseases. The U.S. has higher mortality rates of coronary heart diseases than Japan. A longitudinal comparison in children of risk factor development in the two countries provides more understanding about the causes of cardiovascular disease and its prevention. Such comparisons have not been reported in the past. ^ In Project HeartBeat!, 506 non-Hispanic white, 136 black and 369 Japanese children participated in the study in the U.S. and Japan from 1991 to 1995. A synthetic cohort of ages 8 to 18 years was composed by three cohorts with starting ages at 8, 11, and 14. A multilevel regression model was used for data analysis. ^ The study revealed that the Japanese children had significantly higher slopes of mean total cholesterol (TC) and high density lipoprotein (HDL) cholesterol levels than the U.S. children after adjusting for age and sex. The mean TC level of Japanese children was not significantly different from white and black children. The mean HDL level of Japanese children was significantly higher than white and black children after adjusting for age and sex. The ratio of HDL/TC in Japanese children was significantly higher than in U.S. whites, but not significantly different from the black children. The Japanese group had significantly lower mean diastolic blood pressure phase IV (DBP4) and phase V (DBP5) than the two U.S. groups. The Japanese group also showed significantly higher slopes in systolic blood pressure, DBP5 and DBP4 during the study period than both U.S. groups. The differences were independent from height and body mass index. ^ The study provided the first longitudinal comparison of blood cholesterol and blood pressure between the U.S. and Japanese children and adolescents. It revealed the dynamic process of these factors in the three ethnic groups. ^