Abstract P253: Genome-Wide Association Study of Electrocardiographic Left Ventricular Hypertrophy among Persons of European Ancestry: the Kaiser Permanente/UCSF GERA Cohort
Electrocardiographic (ECG)-derived left ventricular hypertrophy (LVH) is a recognized phenotype of hypertensive target organ damage and an independent risk factor for cardiovascular disease morbidity and mortality, and has been shown to be 20 to 40% heritable. A major prior collaborative study (EchoGen) relied on echocardiography measurement of LVH. We report here the results of the first genome-wide association study of an ECG index of LVH, the Cornell voltage, in a large US, population-based cohort. The Kaiser Permanente/UCSF Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort enrolled 110,266 persons, of whom 84,760 (77%) were of European ancestry (EA). Twelve-lead ECGs (obtained as part of routine medical care) were available in 59% (n=52,423; 62% female, mean age ± SD, 62 ± 13 years) of EA members of the GERA cohort. For those with more than 1 ECG (75%), one was selected at random. We programmatically derived from the digital tracings the Cornell voltage as R in aVL plus S in V3 (in mV). Mean ± SD Cornell voltages were 1.39 ± 0.58 mV in men and 1.16 ± 0.55 mV in women. Genotypes were generated on 674,518 SNPs using a custom designed Affymetrix Axiom array, and imputation was conducted using the 1000 Genomes data as a reference set. We identified 10 genetic loci (nearest genes: NFIA, CRIM1, CCDC141, HAND1, VGLL2, CTNNA, TBX3, SIPA1L1, ZNF595, and PROCR) with genome-wide significant associations (p<5*10-8) with Cornell voltage as a continuous variable. Five of the loci (NFIA, CRIM1, HAND1, TBX3, and SIPA1L1) have previously been reported to influence QRS and PR intervals, while the other loci are novel. Interestingly, none of these loci were associated with left ventricular mass in the EchoGen consortium. Sex-specific analyses supported the association of these loci in both men and women; six loci were associated at a genome-wide significant level in these stratified analyses, including TBX3 and ZNF595 in both men and women, CCDC141, SIPA1L1, and PROCR in men, and VGLL2 in women, despite reduced sample sizes. These results may help elucidate both the biological and genetic basis of this clinically relevant phenotype.
Author Disclosures: C. Iribarren: None. L. Shen: None. A.D. Round: None. E. McNulty: None. P.M. Okin: None. N. Risch: None. C. Schaefer: None. E. Jorgenson: None.
- © 2014 by American Heart Association, Inc.