Four genetic loci influencing electrocardiographic indices of left ventricular hypertrophy

Abstract

Background: Presence of left ventricular hypertrophy on an ECG (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 4 commonly measured indices of ECG-LVH.

Methods and results: We calculated the 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 customized 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 4 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 the 12-lead QRS voltage sum. The odds ratio of being in the top decile for the 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 to 1 alleles was 1.60 (95% CI: 1.20 to 2.29). Lead single-nucleotide polymorphisms at the 12q13.3 and 15q25.2 loci showed significant expression quantitative trait loci 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.

Figure 1. Genetic association of four loci with ECG indices of left ventricular hypertrophy

Forest plots for SNPs showing replicated association with a specific ECG index of LVH: (A) rs6797133 ((SCN5A locus) with Cornell Product; (B) rs2290893 (PTGES3) with QRS Sum; (C) rs2292462 (NMB) with QRS Sum; (D) rs4966014 (IGF1R) with QRS Sum. In each panel associations are reported by study separately for the discovery and replication cohorts, together with pooled estimates for discovery, replication and overall. Beta coefficients (with 95% confidence intervals) describe per allele effect of the minor allele of the SNP for the trait shown. A negative beta indicates that the trait had a lower value in those carrying the minor allele. The I² value shown in the bottom left hand for each panel is the heterogeneity index for results in the meta-analysis of all studies.

Figure 2. Regional association plots of loci associated with indices of ECG-LVH

Each plot shows a region of the relevant chromosome on the X-axis together with association p values from the discovery study meta-analysis for individual SNPs genotyped on the IBC array on the Y-axis. The lead SNP (one showing the strongest association) for each locus is shown as a large red diamond with its corresponding p value. The other SNPs are colour-coded according to their extent of LD (r²) with the lead SNP with bright red indicating high (> 0.9) LD (see scale). The two vertical dotted lines on each panel mark the segment containing SNPs with an LD > 0.5 with the lead SNP. The identity of genes within each region and their location are shown in green below the x-axis. The blue vertical lines identify locations of recombination hot spots with the height of the lines indicating the degree of recombination activity. Panel A: 3p22.2 (SCN5A) locus for Cornell Product; Panel B: 12q13.3 (PTGES3) locus for QRS Sum; Panel C: 15q25.2 (NMB) locus for QRS Sum; Panel D: 15q26.3 (IGF1R) locus for QRS Sum.

Figure 3. Odds Ratios for being in the top decile for the associated trait per carriage of a copy of a trait-raising allele for each of the four novel ECG-LVH loci

Data from meta-analysis of all three discovery cohorts are shown and represented as odds ratio (95% CI) and association p-value.

Figure 4. Meta analysis of the Odds Ratio for being in the top decile for QRS Voltage Sum decile for increasing carriage of trait raising alleles at the three loci associated with QRS Voltage Sum

The group carrying 0–2 alleles was used as the reference group. Data shows the odds ratio and 95% CI of per allele count of the three SNPs associated with this trait (rs2290893, rs2292462, rs4966014). The combined discovery cohort frequencies by allele group are shown in the table within the figure.