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 electrocardiographic PR interval reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation (AF). To identify new underlying common genetic variation associated with PR interval, SardiNIA joined new giant consortium PRIMA for meta-analysis of GWAS results from 33 community-based studies of European-ancestry individuals (N80,000). We identified nine loci associated with PR interval at P <5 x 10(-8). At the 3p22.2 locus, we observed two independent associations in voltage-gated sodium channel genes, SCN10A and SCN5A. Among the others, six of the loci were near cardiac developmental genes, including CAV1-CAV2, NKX2-5 (CSX1), SOX5, WNT11, MEIS1, and TBX5-TBX3. Five of the loci, SCN5A, SCN10A, NKX2-5, CAV1-CAV2, and SOX5, were also associated with atrial fibrillation (N = 5,741 cases, P <0.0056). This suggests a role for common variation in ion channel and developmental genes in atrial and atrioventricular conduction as well as in susceptibility to atrial fibrillation. 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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000799-05
Application #
8736629
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2013
Total Cost
$211,633
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code