Genome-Wide Associations of Global Electrical Heterogeneity ECG Phenotype: The ARIC (Atherosclerosis Risk in Communities) Study and CHS (Cardiovascular Health Study).

Autor: Tereshchenko LG; Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR tereshch@ohsu.edu arking@jhmi.edu.; Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD., Sotoodehnia N; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA., Sitlani CM; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA., Ashar FN; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD., Kabir M; Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR., Biggs ML; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA.; Department of Biostatistics, University of Washington, Seattle, WA., Morley MP; Penn Cardiovascular Institute and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA., Waks JW; Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center Harvard Medical School, Boston, MA., Soliman EZ; Cardiology Section, Division of Public Health Sciences and Department of Medicine, Epidemiological Cardiology Research Center, Wake Forest School of Medicine, Winston Salem, NC., Buxton AE; Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center Harvard Medical School, Boston, MA., Biering-Sørensen T; Brigham and Women's Hospital, Harvard Medical School, Boston, MA., Solomon SD; Brigham and Women's Hospital, Harvard Medical School, Boston, MA., Post WS; Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD., Cappola TP; Penn Cardiovascular Institute and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA., Siscovick DS; The New York Academy of Medicine, New York, NY., Arking DE; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD tereshch@ohsu.edu arking@jhmi.edu.
Jazyk: angličtina
Zdroj: Journal of the American Heart Association [J Am Heart Assoc] 2018 Apr 05; Vol. 7 (8). Date of Electronic Publication: 2018 Apr 05.
DOI: 10.1161/JAHA.117.008160
Abstrakt: Background: ECG global electrical heterogeneity (GEH) is associated with sudden cardiac death. We hypothesized that a genome-wide association study would identify genetic loci related to GEH.
Methods and Results: We tested genotyped and imputed variants in black (N=3057) and white (N=10 769) participants in the ARIC (Atherosclerosis Risk in Communities) study and CHS (Cardiovascular Health Study). GEH (QRS-T angle, sum absolute QRST integral, spatial ventricular gradient magnitude, elevation, azimuth) was measured on 12-lead ECGs. Linear regression models were constructed with each GEH variable as an outcome, adjusted for age, sex, height, body mass index, study site, and principal components to account for ancestry. GWAS identified 10 loci that showed genome-wide significant association with GEH in whites or joint ancestry. The strongest signal (rs7301677, near TBX3 ) was associated with QRS-T angle (white standardized β+0.16 [95% CI 0.13-0.19]; P =1.5×10 -26 ), spatial ventricular gradient elevation (+0.11 [0.08-0.14]; P =2.1×10 -12 ), and spatial ventricular gradient magnitude (-0.12 [95% CI -0.15 to -0.09]; P =5.9×10 -15 ). Altogether, GEH-SNPs explained 1.1% to 1.6% of GEH variance. Loci on chromosomes 4 (near HMCN2 ), 5 ( IGF1R ), 11 (11p11.2 region cluster), and 7 (near ACTB ) are novel ECG phenotype-associated loci. Several loci significantly associated with gene expression in the left ventricle ( HMCN2 locus-with HMCN2 ; IGF1R locus-with IGF1R ), and atria ( RP11-481J2.2 locus-with expression of a long non-coding RNA and NDRG4 ).
Conclusions: We identified 10 genetic loci associated with ECG GEH. Replication of GEH GWAS findings in independent cohorts is warranted. Further studies of GEH-loci may uncover mechanisms of arrhythmogenic remodeling in response to cardiovascular risk factors.
(© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)
Databáze: MEDLINE
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