1) PWV, a noninvasive index of central arterial stiffness, is a potent predictor of cardiovascular mortality and morbidity. Our recent publications confirmed the presence of a genetic component affecting PWV. Recently SardiNIA has joined international consortium Aorta-Gen (25000 individuals) for finer mapping of previously determined and identification of new loci associated with PWV. We have identified a new locus on desert region of Chromosome 14 in the conserved core region of the BCL11B gene enhancer that is associated with CFPWV. We have performed expression analysis of human and mouse tissues for detection of ESTs from the region of association. Further elucidation of the role that this novel locus plays in aortic stiffness may facilitate the development of specific therapeutic interventions that reduce or prevent aortic stiffening and related cardiovascular disease events. 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) Elevated resting heart rate has been associated with increased risk of cardiovascular diseases and mortality. Our previous GWA study has identified seven loci for heart rate and much of its heritability remains unexplained. To identify additional loci affecting heart rate, SardiNIA joined stage 2 of international heart-rate consortium (total of 181178 individuals) to examine associations between 2.55 million SNPs and resting heart rate. Lead variants from 42 loci (p<2x10-5) in the discovery cohort were followed up in additional individuals from stage 2. Combined analyses of stage 1 and stage 2 results identified associations with heart rate for variants in 21 loci (p<5x10-8), including 14 new loci and the seven previously established ones. Some of the newly identified loci map near genes in which mutations have previously been associated with cardiovascular diseases (CALCRL, TTN, HCN4, CHRM2, FLRT2, NKX2-5). Many of the confirmed loci harbor genes that point toward promising pathways that may provide new insights into the mechanisms regulating heart rate in health and disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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van der Harst, Pim; van Setten, Jessica; Verweij, Niek et al. (2016) 52 Genetic Loci Influencing Myocardial Mass. J Am Coll Cardiol 68:1435-1448
Scuteri, Angelo; Morrell, Christopher H; Orru', Marco et al. (2016) Gender specific profiles of white coat and masked hypertension impacts on arterial structure and function in the SardiNIA study. Int J Cardiol 217:92-8
Ehret, Georg B (see original citation for additional authors) (2016) The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals. Nat Genet 48:1171-1184
Beygui, Farzin; Wild, Philipp S; Zeller, Tanja et al. (2014) Adrenomedullin and arterial stiffness: integrative approach combining monocyte ADM expression, plasma MR-Pro-ADM, and genome-wide association study. Circ Cardiovasc Genet 7:634-41
Arking, Dan E (see original citation for additional authors) (2014) Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization. Nat Genet 46:826-36
Terracciano, Antonio; Strait, James; Scuteri, Angelo et al. (2014) Personality traits and circadian blood pressure patterns: a 7-year prospective study. Psychosom Med 76:237-43
Sabater-Lleal, Maria; Huang, Jie; Chasman, Daniel et al. (2013) Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease. Circulation 128:1310-24
den Hoed, Marcel (see original citation for additional authors) (2013) Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders. Nat Genet 45:621-31
Scuteri, Angelo; Lakatta, Edward G (2013) Bringing prevention in geriatrics: evidences from cardiovascular medicine supporting the new challenge. Exp Gerontol 48:64-8
Naitza, Silvia; Porcu, Eleonora; Steri, Maristella et al. (2012) A genome-wide association scan on the levels of markers of inflammation in Sardinians reveals associations that underpin its complex regulation. PLoS Genet 8:e1002480

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