Abstract
BackgroundElectrocardiographic measures of left ventricular hypertrophy (LVH) are used as predictors of cardiovascular risk. We combined linkage and association analyses to discover novel rare genetic variants involved in three such measures and two principal components derived from them.MethodsThe study was conducted among participants from the Erasmus Rucphen Family Study (ERF), a Dutch family-based sample from the southwestern Netherlands. Variance components linkage analyses were performed using Merlin. Regions of interest (LOD > 1.9) were fine-mapped using microarray and exome sequence data.ResultsWe observed one significant LOD score for the second principal component on chromosome 15 (LOD score = 3.01) and 12 suggestive LOD scores. Several loci contained variants identified in GWAS for these traits; however, these did not explain the linkage peaks, nor did other common variants. Exome sequence data identified two associated variants after multiple testing corrections were applied.ConclusionsWe did not find common SNPs explaining these linkage signals. Exome sequencing uncovered a relatively rare variant in MAPK3K11 on chromosome 11 (MAF = 0.01) that helped account for the suggestive linkage peak observed for the first principal component. Conditional analysis revealed a drop in LOD from 2.01 to 0.88 for MAP3K11, suggesting that this variant may partially explain the linkage signal at this chromosomal location. MAP3K11 is related to the JNK pathway and is a pro-apoptotic kinase that plays an important role in the induction of cardiomyocyte apoptosis in various pathologies, including LVH.
Highlights
Electrocardiographic measures of left ventricular hypertrophy (LVH) are used as predictors of cardiovascular risk
Two regions were suggestively linked to PC1: 11q13.4 (LOD = 2.01) and 20p12.1 (LOD = 2.83), which was linked to Sokolow-Lyon index (SL) and 12-lead sum QRS product (12LS)
Jun N-terminal kinase (JNK), an important member of the mitogen-activated protein kinase family (MAPK), is a pro-apoptotic kinase that plays an important role in the induction of cardiomyocyte apoptosis in various pathologies [43]
Summary
Electrocardiographic measures of left ventricular hypertrophy (LVH) are used as predictors of cardiovascular risk. Left ventricular hypertrophy (LVH) is a predictor of increased cardiovascular morbidity and mortality [1]. Those with LVH have a 2-fold increased risk of adverse events, ischemic heart disease and chronic heart failure [2, 3]. An expanded GWAS detected a number of novel loci influencing CV, SL, and 12LS [11] Among these were 32 loci containing genes with known cardiac function, coding for cardiac sarcomere components or related to cardiac myocyte function. As is the case for other complex outcomes, most candidate genes studies have not been replicated and do not reach genome-wide significance [3]
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