29Whole genome and transcriptome approach in a polygenic model for cardiac hypertrophy identifies Trim55 as a new candidate gene in quantitative trait locus cardiac mass 22

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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.

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