Dataset Information

Putative functional genes in idiopathic dilated cardiomyopathy.

ABSTRACT: Idiopathic dilated cardiomyopathy (DCM) is a complex disorder with a genetic and an environmental component involving multiple genes, many of which are yet to be discovered. We integrate genetic, epigenetic, transcriptomic, phenotypic, and evolutionary features into a method - Hridaya, to infer putative functional genes underlying DCM in a genome-wide fashion, using 213 human heart genomes and transcriptomes. Many genes identified by Hridaya are experimentally shown to cause cardiac complications. We validate the top predicted genes, via five different genome-wide analyses: First, the predicted genes are associated with cardiovascular functions. Second, their knockdowns in mice induce cardiac abnormalities. Third, their inhibition by drugs cause cardiac side effects in human. Fourth, they tend to have differential exon usage between DCM and normal samples. Fifth, analyzing 213 individual genotypes, we show that regulatory polymorphisms of the predicted genes are associated with elevated risk of cardiomyopathy. The stratification of DCM patients based on cardiac expression of the functional genes reveals two subgroups differing in key cardiac phenotypes. Integrating predicted functional genes with cardiomyocyte drug treatment experiments reveals novel potential drug targets. We provide a list of investigational drugs that target the newly identified functional genes that may lead to cardiac side effects.

SUBMITTER: Nair NU

PROVIDER: S-EPMC5758757 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Putative functional genes in idiopathic dilated cardiomyopathy.

Nair Nishanth Ulhas NU Das Avinash A Amit Uri U Robinson Welles W Park Seung Gu SG Basu Mahashweta M Lugo Alex A Leor Jonathan J Ruppin Eytan E Hannenhalli Sridhar S

Scientific reports 20180108 1

Idiopathic dilated cardiomyopathy (DCM) is a complex disorder with a genetic and an environmental component involving multiple genes, many of which are yet to be discovered. We integrate genetic, epigenetic, transcriptomic, phenotypic, and evolutionary features into a method - Hridaya, to infer putative functional genes underlying DCM in a genome-wide fashion, using 213 human heart genomes and transcriptomes. Many genes identified by Hridaya are experimentally shown to cause cardiac complication ...[more]

PMID: 29311597

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Project description:ImportanceIdiopathic dilated cardiomyopathy (DCM) aggregates in families, and early detection in at-risk family members can provide opportunity to initiate treatment prior to late-phase disease. Most studies have included only White patients, yet Black patients with DCM have higher risk of heart failure-related hospitalization and death.ObjectiveTo estimate the prevalence of familial DCM among DCM probands and the age-specific cumulative risk of DCM in first-degree relatives across race and ethnicity groups.Design, setting, and participantsA family-based, cross-sectional study conducted by a multisite consortium of 25 US heart failure programs. Participants included patients with DCM (probands), defined as left ventricular systolic dysfunction and left ventricular enlargement after excluding usual clinical causes, and their first-degree relatives. Enrollment commenced June 7, 2016; proband and family member enrollment concluded March 15, 2020, and April 1, 2021, respectively.ExposuresThe presence of DCM in a proband.Main outcomes and measuresFamilial DCM defined by DCM in at least 1 first-degree relative; expanded familial DCM defined by the presence of DCM or either left ventricular enlargement or left ventricular systolic dysfunction without known cause in at least 1 first-degree relative.ResultsThe study enrolled 1220 probands (median age, 52.8 years [IQR, 42.4-61.8]; 43.8% female; 43.1% Black and 8.3% Hispanic) and screened 1693 first-degree relatives for DCM. A median of 28% (IQR, 0%-60%) of living first-degree relatives were screened per family. The crude prevalence of familial DCM among probands was 11.6% overall. The model-based estimate of the prevalence of familial DCM among probands at a typical US advanced heart failure program if all living first-degree relatives were screened was 29.7% (95% CI, 23.5% to 36.0%) overall. The estimated prevalence of familial DCM was higher in Black probands than in White probands (difference, 11.3% [95% CI, 1.9% to 20.8%]) but did not differ significantly between Hispanic probands and non-Hispanic probands (difference, -1.4% [95% CI, -15.9% to 13.1%]). The estimated prevalence of expanded familial DCM was 56.9% (95% CI, 50.8% to 63.0%) overall. Based on age-specific disease status at enrollment, estimated cumulative risks in first-degree relatives at a typical US advanced heart failure program reached 19% (95% CI, 13% to 24%) by age 80 years for DCM and 33% (95% CI, 27% to 40%) for expanded DCM inclusive of partial phenotypes. The DCM hazard was higher in first-degree relatives of non-Hispanic Black probands than non-Hispanic White probands (hazard ratio, 1.89 [95% CI, 1.26 to 2.83]).Conclusions and relevanceIn a US cross-sectional study, there was substantial estimated prevalence of familial DCM among probands and modeled cumulative risk of DCM among their first-degree relatives.Trial registrationClinicalTrials.gov Identifier: NCT03037632.

Dataset Information

Putative functional genes in idiopathic dilated cardiomyopathy.

Publications

Putative functional genes in idiopathic dilated cardiomyopathy.

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