1) Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rateincreasing and heart ratedecreasing variants associate with risk of atrial fibrillation.. 2) The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain 810% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT intervalassociated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD. 3) Common genetic variants have recently been identified through the aggregation of GWAS in large sample size, but in total these variants explain a small fraction of the heritable contribution to BP variation. For further investigation of variants associated with BP variation SardiNIA study has joined new IGCBP consortium using meta-analysis of CardioMetaboChip and IGCBP GWAS. The discovery meta-analysis includes up to 201,528 European ancestry individuals from 50 studies. In total we identify 67 genome-wide significant loci, at which at least one common variant is associated in our data. Of these 67 loci, 28 were not reported previously and 39 have been previously reported in the literature. 4) Ambulatory blood pressure records have been obtained for nearly all SardiNIA participants and epidemiologic analysis has been completed. A second round of deeper genetic sequencing is being completed that will be used to buttress genetic association findings and identify potential causal variants; at which point manuscripts will be prepared. 5) A number of epidemiologic findings have been associated with early repolarization which were presented at the national American College of Cardiology Conference as well as editorialized in the online ACC/Heart Rhythm Society journal (http://crm.cardiosource.org/Learn-from-the-Experts/2012/07/Early-Repolarization-Pattern-on-Electrocardiogram.aspx). Genetic associations have been identified but replication in a subset of SardiNIA subjects will be needed for confirmation and so an additional 2000 EKGs are being assessed at this time. 6) We found evidence that reduced nighttime blood pressure dipping is associated with antagonism and impulsivity-related traits but not with measures of emotional vulnerability. The strongest associations were found with conscientiousness, a trait that may have a broad impact on cardiovascular health. 7) The research protocol has been modified to simultaneously acquire echocardiography, Doppler signals, and applanation tonometry to enable integrations of pressure, flow, and geometry signals and derive the aforementioned parameters. Mathematical analysis of the signals collected will be performed by the of 4th wave and GWAS analysis of the advanced traits will be conducted. We found, that SNP located in Adrenomedullin (ADM) gene rs11042717/TT independently associated with reduced Reflection Index (P<104 and P=0.009) and Stiffness Index (r=0.52; P<104 after adjustment for risk factors). These findings support an involvement of the ADM gene in the modulation of peripheral vascular tone.
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