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Objectives: Genes implicated in monogenic human cardiac hypertrophy (CH) might also be involved in the more common polygenic forms. The Hypertrophic Heart Rat (HHR) is a unique normotensive model of spontaneous polygenic ventricular hypertrophy leading to cardiac failure and premature death. Our aim was to survey mRNA expression and genetic variants in genes previously associated with monogenic forms of dilated and hypertrophic cardiomyopathy in humans utilising the HHR.Design and methods: We used Affymetrix GeneChip® Rat Gene 1.0 ST arrays to measure whole-genome mRNA in left ventricles of HHR and its normal control, the Normal Heart Rat (NHR) (n=8 per group). We also performed whole-genome DNA sequencing of both strains using the HiSeq 2000 platform. We aligned and compared sequences to the Rat Genome Database v3.4 and identified four types of variants: SNPs, insertions and deletions (InDels), copy number variations (CNVs) and structural variants (SVs).Results: We found 15 (Cryab, Dsg2, Lama4, Mybpc3, Myh6, Myh7,Myl2, Nexn, Psen2, Rbm20, Tnnc1, Tnni3, Tnnt2, Tpm1, Ttn) of the initial known 40 candidate genes significantly differentially expressed in the HHR (FDR<0.05). Their fold change was small (∼1.3) consistent with a polygenic contribution. Overall, we found 182 variants unique to the HHR in our gene subset. Most variants were SNPs (n=101), followed by InDels (n=67), CNVs (n=12) and SVs (n=2). No major mutations typical of human monogenic cardiomyopathies were found. The majority of SNPs are located in non-coding regions (n=98) except for two variants in the coding region for the gene for troponin T type 2 (Tnnt2) and one in its 3' untranslated region. Interestingly, both mutations in the coding region are synonymous and do not cause a change in the amino acid or protein sequence. Although the variants found in gene for Tnnt2 are synonymous, silent mutations may alter gene expression levels by transfer RNA availability and influence phenotypically variability.Conclusions: Our study is the first to show that genes involved in monogenic human forms of hypertrophy may also contribute through changed expression and subtle variants in DNA sequence to the common polygenic form of left ventricular hypertrophy. [ABSTRACT FROM AUTHOR]

Objective: Cardiac hypertrophy (CH) is the main risk factor for heart disease after age. Multiple genetic factors are known to be involved but still poorly understood. We have previously described a quantitative trait locus (QTL) cardiac mass 22 (Cm22) on chromosome 2 which influences heart size independently of blood pressure. Our aim was to determine which genes in QTL Cm22 contribute to CH using a polygenic genetic model.Design and method: We used a genomic and transcriptomic approach to identify genes in Cm22 contributing to CH. Firstly, we used the Illumina HiSeq 2000 platform to sequence the whole-genome of the Hypertrophic Heart Rat (HHR), a normotensive genetic model of CH, and its control, the Normal Heart Rat (NHR). Both genomes were aligned and compared to Rat Genome Database v3.4 and four types of variants were analysed: single nucleotide polymorphisms (SNPs), insertions and deletions (InDels), copy number variations (CNVs) and structural variants (SVs). Secondly, we investigated gene expression of all Cm22 genes in left ventricles of HHR and NHR (n=8 per group) using Affymetrix GeneChip® Rat Gene 1.0 ST arrays. We then combined these data to identify unique variants in genes differentially expressed in QTL Cm22.Results: Overall, approximately 5.7 and 5 million variants are present in HHR and NHR, respectively, and the majority of the variants (80%) were SNPs. In QTL Cm22, we found approximately 10 thousand variants in each strain. The array data showed that gene for tripartite motif-containing 55 (Trim55) was significantly downregulated in HHR (FC=-2.08; FDR=0.049). We validated these findings by real-time polymerase chain reaction (qPCR), which showed that Trim55 mRNA is down-regulated from neonatal to late adulthood in the CH model.Analysis of the gene region of Trim55 identified 12 and 24 variants in HHR and NHR, respectively. One missense mutation in the HHR was located in its ninth exon. In silico studies demonstrated that this mutation may cause a change in the protein structure which may affect function.Conclusion: The Trim55 gene in QTL CM22 is a novel candidate gene for polygenic hypertrophy development independent of blood pressure. [ABSTRACT FROM PUBLISHER]