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Six New Sporadic Dilated Cardiomyopathy Risk Loci Detected

NEW YORK (GenomeWeb) – An international team led by investigators in France has used an exome-wide association study approach to detect half a dozen new loci with apparent ties to dilated cardiomyopathy risk, a new study suggests.

As they reported in PLOS One yesterday, the researchers did array-based exome profiling on nearly 2,800 individuals with dilated cardiomyopathy. Compared with protein-coding sequence patterns in thousands of unaffected controls form the same populations, they picked up associations between dilated cardiomyopathy and variants at eight loci — a set that included six new loci and two parts of the genome that had been linked to the heart muscle condition in the past.

"[W]e confirmed associations with variants in ZBTB17-HSPB7 and BAG3 and identified six novel loci," co-senior authors Eric Villard and François Cambien, researchers with the French National Institute of Health and medical Research (INSERM), and their co-authors wrote. "Statistical analyses, cardiac tissue expression, and physiology suggest that the most likely causal genes are HSPB7, BAG3, TTN, SLC39A8, MLIP, FLNC, ALPK3, and FHOD3."

Prior genetic studies have uncovered common and rare genetic variants that may account for some of the heritability of dilated cardiomyopathy, a condition that can lead to heart failure or sudden cardiac death. For their new analysis, Villard, Cambien, and their colleagues searched for variants contributing to dilated cardiomyopathy in individuals of European descent from six populations in the US, Germany, France, the UK, and Italy.

Using Illumina HumanExome BeadChip arrays, the team genotyped 2,796 individuals with dilated cardiomyopathy and 6,877 unaffected control individuals, identifying 11 SNPs at eight loci that were suspected of influencing susceptibility to the heart condition.

The same loci turned up after the researchers removed samples from 85 individuals with familial forms of dilated cardiomyopathy, while their fine-mapping helped narrow in on genes that appeared to have the most pronounced effects on dilated cardiomyopathy risk. For example, their results pointed to potential roles for genes in heat shock response, muscle, transport, and other pathways.

The team's gene-based analysis of dilated cardiomyopathy-related rare variants again led to genes at the ZBTB17, TTN, and BAG3 loci. Meanwhile, an analysis of four-dozen genes and hundreds of variants linked to familial dilated cardiomyopathy hinted that variants involved in familial forms of the disease likely contribute to sporadic dilated cardiomyopathy cases as well, the authors noted, "indicating that the spectrum of genes contributing to sporadic [dilated cardiomyopathy] extends beyond those identified here."

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