Four Genetic Loci Influencing Electrocardiographic Indices of Left Ventricular Hypertrophy

Abstract

Background Presence of left ventricular hypertrophy on an electrocardiogram (ECG-LVH) is widely assessed clinically and provides prognostic information in some settings. There is evidence for significant heritability of ECG-LVH. We conducted a large-scale gene-centric association analysis of four commonly measured indices of ECG-LVH. Methods and Results We calculated Sokolow-Lyon Index, Cornell Product, 12-lead QRS Voltage Sum and 12-lead QRS Voltage Product in 10,256 individuals from 3 population based cohorts and typed their DNA using a customised gene array (the Illumina HumanCVD BeadChip 50K array) containing 49,094 genetic variants in ~2100 genes of cardiovascular relevance. We followed up promising associations in 11,777 additional individuals. We identified and replicated four loci associated with ECG-LVH indices - 3p22.2 (SCN5A, rs6797133, p=1.22×10−7) with Cornell Product and 12q13.3 (PTGES3, rs2290893, p=3.74×10−8), 15q25.2 (NMB, rs2292462, p=3.23×10−9) and 15q26.3 (IGF1R, rs4966014, p=1.26×10−7) with 12-lead QRS Voltage Sum. The odds ratio of being in the top decile for 12-lead QRS Voltage Sum for those carrying 6 trait-raising alleles at the 12q13.3, 15q25.2 and 15q26.3 loci versus those carrying 0–1 alleles was 1.60 (95% CI: 1.20 – 2.29). Lead SNPs at the 12q13.3 and 15q25.2 loci showed significant eQTL effects in monocytes. Conclusions These findings provide novel insights into the genetic determination of ECG-LVH. The findings could help to improve our understanding of the mechanisms determining this prognostically important trait.

Advances in Blood Pressure Genomics

“…This array included SNPs not captured by earlier genome-wide chips, and this additional content has not only led to discovery of new blood pressure genes but also added to gene discovery for other cardiovascular traits. [49][50][51] Table 2 lists the SNPs associated with blood pressure traits which have been robustly validated to date.…”

Genetic association of left ventricular mass assessed by M-mode and two-dimensional echocardiography

“…Electrocardiographically determined LVH has been long associated with cardiovascular events [45] and early hypertension trials have shown regression of electrocardiographic LVH with treatment [46]. To our knowledge, only one genome-wide study identified associations with electrocardiographic indices of LVH in discovery and replications cohorts including 22,033 subjects [47]. However, since electrocardiographically determined LVH is insensitive to identify individuals with LVH, echocardiography has supplanted electrocardiography for the characterization of LV mass in clinical care and in research.…”

A functional variant in the coding region of CAMTA2 is associated with left ventricular hypertrophy by affecting the activation of Nkx2.5-dependent transcription

“…Cardiac hypertrophy, defined as an increase in the size and/or thickness of the ventricles in the heart, is an important compensatory mechanism for pathophysiological states and an independent predictor of cardiovascular morbidity and mortality [20,21]. Recently, several genomewide association studies (GWASs) for LVH have been reported [22][23][24][25][26][27]; however, the association of rs238234 in CAMTA2 with LVH did not reach genome-wide significance levels. There are some reasons to explain: first, many variants with the biological characteristics are filtered out because GWASs employed the rigorous statistics correction and P value to identify the most statistically significant single-nucleotide polymorphisms between case and control.…”