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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.

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.

Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped ∼50 000 single-nucleotide polymorphisms (SNPs) that capture variation in ∼2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed 10 previously known loci associated with SBP, DBP, MAP or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P < 2.4 × 10(-6)). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention.

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.

Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.4 × 10(-6)), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 × 10(-8)). Common variants with minor allele frequencies greater than 5% were observed to be associated with height in 37 previously reported loci. In individuals of European ancestry, uncommon SNPs in IL11 and SMAD3, which would not be genotyped with the use of standard genome-wide genotyping arrays, were strongly associated with height (p < 3 × 10(-11)). Conditional analysis within associated regions revealed five additional variants associated with height independent of lead SNPs within the locus, suggesting allelic heterogeneity. Although underpowered to replicate findings from individuals of European ancestry, the direction of effect of associated variants was largely consistent in African American, South Asian, and Hispanic populations. Overall, we show that dense coverage of genes for uncommon SNPs, coupled with large-scale meta-analysis, can successfully identify additional variants associated with a common complex trait.

Background: Although the prevalence of obesity is increasing during adulthood, there have been few assessments of obesity, cardiovascular risk factors, and levels of physical activity among adult elementary school staff. Methods: Data were collected from 745 African-American and White female school personnel in a suburban school district in southeastern Louisiana as part of the baseline assessment before implementation of a program to improve eating and physical activity behaviors. Anthropometry, blood pressure, serum lipids and lipoproteins, and glucose were measured using established protocols. Physical activity was assessed by accelerometry. Results: For both White and Black females, 30% were overweight (body mass index [BMI]) greater than or equal to 25 kg/m[superscript 2] but less than 30 kg/m[superscript 2]). Whereas 37% of White females were obese (BMI greater than or equal to 30 kg/m[superscript 2]), 61% of the Black females were obese. There was a positive association between BMI and other cardiovascular risk factors except for high-density lipoprotein cholesterol, where the association was negative. The mean number of minutes of daily moderate-to-vigorous physical activity was less than 1 minute per day and was lower for overweight and obese women than for normal weight women. Conclusions: School personnel in the study have adverse cardiovascular risk factors, including high rates of obesity and very low levels of physical activity. Because these individuals are often called upon to promote health for children, they are an important target population for wellness interventions. (Contains 4 tables and 1 figure.)

OBJECTIVE. This study sought to examine the usefulness of non-high-density lipoprotein cholesterol levels in predicting future dyslipidemia and other cardiovascular risk in adulthood. METHODS. The study sample consisted of a longitudinal cohort of subjects (n = 1163; 30.1% black and 55.4% female) who participated in the Bogalusa Heart Study both as children at 5 to 14 years of age and as adults 27 years later. RESULTS. The childhood level of non-high-density lipoprotein cholesterol, like low-density lipoprotein cholesterol, was the best predictor of the adulthood level; the next best predictor for both variables was the change in BMI from childhood to adulthood. Furthermore, those in the age-, race-, and gender-specific top quartile, compared with those in the bottom quartile, of non-high-density lipoprotein cholesterol and low-density lipoprotein cholesterol levels in childhood were 4.5 and 3.5 times more likely, respectively, to develop adult dyslipidemia, independent of baseline BMI and BMI change after 27 years. Although, at equivalent cutoff points, childhood high-risk versus acceptable-risk status for both lipid measures was associated significantly with increased prevalence of obesity and adverse levels of low-density lipoprotein cholesterol and triglycerides in adulthood, only childhood non-high-density lipoprotein cholesterol high-risk status was associated with increased prevalence of low high-density lipoprotein cholesterol levels, hyperinsulinemia, and hyperglycemia (marginal). CONCLUSIONS. Adverse levels of non-high-density lipoprotein cholesterol versus low-density lipoprotein cholesterol in childhood not only equally persist over time and better predict adult dyslipidemia but also are related to nonlipid cardiovascular risk factors in adulthood. www.pediatrics.org/cgi/doi/10.15421 peals.2005-1856 doi:10.15421peds.2005-1856 Key Words non-high-density lipoprotein cholesterol, low-density liDoorotein cholesterol, childhood, adulthood, tracking, coronary artery disease risk Abbreviations CAD--coronary artery disease HDL--high-density lipoprotein LDL--low-density lipoprotein, ADVERSE LEVELS OF serum lipoprotein cholesterols have long been recognized as an important risk factor for coronary artery disease (CAD) among adults. (1) Furthermore, adverse levels among youths are associated [...]

Objectives. In adult populations, it is recognized widely that waist circumference (WC) predicts health risk beyond that predicted by BMI alone; current recommendations for adults are that a combination of BMI and WC be used to classify obesity-related health risk. For children and adolescents, however, little is known about the combined influence of BMI and WC on health outcomes. The objectives of this study were to determine whether BMI and WC predict coronary artery disease (CAD) risk factors independently for children and adolescents and to assess the clinical utility of using WC in combination with BMI to identify CAD risk. Methods. Subjects included 2597 black and white, 5- to 18-year-old, male and female youths. Outcome measures included 7 CAD risk factors. In the first analysis step, BMI and WC were used as continuous variables to predict CAD risk factors. In the second analysis step, participants were placed into normal-weight, overweight, and obese BMI categories and, within each BMI category, CAD risk factors were compared for groups with low and high WC values. Results. When BMI and WC were included in the same regression model to predict CAD risk factors, the added variance above that predicted by BMI or WC alone was minimal, which indicated that BMI and WC did not have independent effects on the risk factors. For example, for systolic blood pressure, BMI alone explained 7.3% of the variance, WC alone explained 7.7% of the variance, and the combination of BMI and WC explained 8.1% of the variance. When BMI and WC values were categorized with a threshold approach, WC provided information on CAD risk beyond that provided by BMI alone, particularly when the categories were used to predict elevated CAD risk factor levels. For instance, in the overweight BMI category, the high-WC group was ~2 times more likely to have high triglyceride levels, high insulin levels, and the metabolic syndrome, compared with the low-WC group. Conclusion. These findings provide some evidence that a combination of BMI and WC should be used in clinical settings to evaluate the presence of elevated health risk among children and adolescents. Pediatrics 2005;115:1623-1630; obesity, body mass index, waist circumference, cholesterol, metabolic syndrome. ABBREVIATIONS. CAD, coronary artery disease; IOTF, International Obesity Task Force; CDC, Centers for Disease Control and Prevention; WC, waist circumference; HDL, high-density lipoprorein; LDL, low-density lipoprotein; OR, odds ratio; CI, confidence interval., The BMI is a predictor of numerous coronary artery disease (CAD) risk factors among children and adolescents, (1,2) and its clinical utility in pediatric populations has been endorsed by numerous [...]

Objective. Although many studies have found that childhood levels of body mass index (BMI; kg/[m.sup.2]) are associated with adult levels, it has been reported that childhood BMI is not associated with adult adiposity. We further examined these longitudinal associations. Design. Cohort study based on examinations between 1973 and 1996. Setting. Bogalusa, Louisiana. Participants. Children (2610; ages 2-17 years old) who were followed to ages 18 to 37 years; the mean follow-up was 17.6 years. Main Outcome Measures. BMI-for-age and triceps skinfold thickness (SF) were measured in childhood. Subscapular and triceps SFs were measured among adults, and the mean SF was used as an adiposity index. Adult obesity was defined as a BMI [greather than or equal to] 30 kg/[m.sup.2] and adult overfat as a mean SF in the upper (gender-specific) quartile. Results. Childhood levels of both BMI and triceps SF were associated with adult levels of BMI and adiposity. The magnitude of these longitudinal associations increased with childhood age, but the BMI levels of even the youngest (ages 2-5 years) children were moderately associated (r = 0.33-0.41) with adult adiposity. Overweight (BMI-for-age [greater than or equal to] 95th centile) 2- to 5-year-olds were >4 times as likely to become overfat adults (15 of 23 [65%]), as were children with a BMI < 50th centile (30 of 201 [15%]). Even after accounting for the triceps SF of children, BMI-for-age provided additional information on adult adiposity. Conclusions. Childhood BMI is associated with adult adiposity, but it is possible that the magnitude of this association depends on the relative fatness of children. Pediatrics 2005;115:22-27; body mass index, obesity, adult adiposity, Bogalusa Heart Study, longitudinal study, skin folds., ABBREVIATIONS. BMI, body mass index; SF, skinfold thickness. Despite the limitations of weight-height indices, (1,2) they are widely used as indicators of adiposity. Several investigators have found that childhood body [...]