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Dilated Cardiomyopathy Processes Informed by Heart Tissue Transcriptomes

NEW YORK (GenomeWeb) – Transcriptome sequences for samples collected during heart transplant proceeds have provided a glimpse at the gene expression, splicing, expression quantitative trait loci, or genetic variant patterns that differ between individuals with and without an inherited heart condition called dilated cardiomyopathy.

Members of an international team led by investigators in the Netherlands, Singapore, and Germany did RNA sequencing on heart samples from 97 heart transplant recipients with dilated cardiomyopathy and 108 healthy heart donors. Their findings, published online today in Genome Biology, pointed to more than 200 differentially expressed genes in the cases and controls.

The team also saw shifting eQTLs in heart samples from the individuals with dilated cardiomyopathy, particularly at sites overlapping with SNPs associated with dilated cardiomyopathy in past genome-wide association studies.

"Although there are already plenty of clinical indications for many cardiovascular diseases, we hope a transcriptome analysis will be able to improve these predictions," co-senior author Norbert Hübner, a cardiovascular and metabolic sciences researcher at the Max-Delbrück Center for Molecular Medicine, said in a statement.

Truncating mutations affecting the titin muscle protein gene TTN are among the most common and well-known alterations contributing to dilated cardiomyopathy, the authors noted, though dozens of genes have been implicated in the condition. They reasoned that a clearer view of dilated cardiomyopathy biology could come from folding in transcriptome profiles from tricky-to-access heart samples.

Using Illumina HiSeq 2000 instruments, the researchers sequenced RNA extracted from left ventricular myocardium samples for 108 healthy heart donors and 97 individuals with dilated cardiomyopathy, providing a look at expression patterns for more than 57,200 genes.

Expression differences turned up for 228 protein-coding genes and 53 non-coding RNAs when they compared the case and control transcriptomes, including some genes linked to dilated cardiomyopathy in the past.

When the team took a look at splicing patterns in heart samples from individuals with or without dilated cardiomyopathy, meanwhile, it narrowed in on exon usage differences involving nearly 900 genes from cytoskeleton organization, actin filament organization, and other pathways.

By bringing together variant and expression data, the researchers identified thousands of apparent eQTLs in the heart samples — a set that included 100 eQTLs specific to the dilated cardiomyopathy group and 128 control heart-specific eQTLs.

They also searched for splicing QTLs, uncovered instances of allelic imbalance shifts in dilated cardiomyopathy, and set the transcriptome findings alongside dilated variants associated with cardiomyopathy or other heart phenotypes in past GWAS.

"The RNA-seq-based QTL data set of [dilated cardiomyopathy] patients and non-diseased donors … revealed marked transcriptome differences between diseased and non-diseased tissue and a widespread effect of genetic variation on the regulation of transcription and splicing," the authors concluded, noting that it "allowed for great improvements in [genome-wide association] candidate gene prioritization, facilitating the elucidation of the mechanisms underlying the genetic basis of common diseases of the heart."

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