Dataset Information

A genetic association study of heart failure: more evidence for the role of BAG3 in idiopathic dilated cardiomyopathy.

ABSTRACT:

Aims

Few investigations have been conducted to identify genetic determinants of common, polygenetic forms of heart failure (HF), and only a limited number of these genetic associations have been validated by multiple groups.

Methods and results

We performed a case-control study to further investigate the potential impact of 14 previously reported candidate genes on the risk of HF and specific HF sub-types. We also performed an exploratory genome-wide study. We included 799 patients with HF and 1529 controls. After adjusting for age, sex, and genetic ancestry, we found that the C allele of rs2234962 in BAG3 was associated with a decreased risk of idiopathic dilated cardiomyopathy (odds ratio 0.42, 95% confidence interval 0.25-0.68, P = 0.0005), consistent with a previous report. No association for the other primary variants or exploratory genome-wide study was found.

Conclusions

Our findings provide independent replication for the association between a common coding variant (rs2234962) in BAG3 and the risk of idiopathic dilated cardiomyopathy.

SUBMITTER: de Denus S

PROVIDER: S-EPMC7754954 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Publications

A genetic association study of heart failure: more evidence for the role of BAG3 in idiopathic dilated cardiomyopathy.

de Denus Simon S Mottet Fannie F Korol Sandra S Feroz Zada Yassamin Y Provost Sylvie S Mongrain Ian I Asselin Géraldine G Oussaïd Essaïd E Busseuil David D Lettre Guillaume G Rioux John J Racine Normand N O'Meara Eileen E White Michel M Rouleau Jean J Tardif Jean Claude JC Dubé Marie-Pierre MP

ESC heart failure 20200901 6

<h4>Aims</h4>Few investigations have been conducted to identify genetic determinants of common, polygenetic forms of heart failure (HF), and only a limited number of these genetic associations have been validated by multiple groups.<h4>Methods and results</h4>We performed a case-control study to further investigate the potential impact of 14 previously reported candidate genes on the risk of HF and specific HF sub-types. We also performed an exploratory genome-wide study. We included 799 patient ...[more]

PMID: 32869539

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Project description:Dilated cardiomyopathy (DCM) is a structural heart disease with strong genetic background. Monogenic forms of DCM are observed in families with mutations located mostly in genes encoding structural and sarcomeric proteins. However, strong evidence suggests that genetic factors also affect the susceptibility to idiopathic DCM. To identify risk alleles for non-familial forms of DCM, we carried out a case-control association study, genotyping 664 DCM cases and 1,874 population-based healthy controls from Germany using a 50K human cardiovascular disease bead chip covering more than 2,000 genes pre-selected for cardiovascular relevance. After quality control, 30,920 single nucleotide polymorphisms (SNP) were tested for association with the disease by logistic regression adjusted for gender, and results were genomic-control corrected. The analysis revealed a significant association between a SNP in HSPB7 gene (rs1739843, minor allele frequency 39%) and idiopathic DCM (p = 1.06 × 10??, OR? = 0.67 [95% CI 0.57-0.79] for the minor allele T). Three more SNPs showed p < 2.21 × 10??. De novo genotyping of these four SNPs was done in three independent case-control studies of idiopathic DCM. Association between SNP rs1739843 and DCM was significant in all replication samples: Germany (n =564, n = 981 controls, p = 2.07 × 10?³, OR?= 0.79 [95% CI 0.67-0.92]), France 1 (n = 433 cases, n = 395 controls, p =3.73 × 10?³, OR? = 0.74 [95% CI 0.60-0.91]), and France 2 (n = 249 cases, n = 380 controls, p = 2.26 × 10??, OR? = 0.63 [95% CI 0.50-0.81]). The combined analysis of all four studies including a total of n = 1,910 cases and n = 3,630 controls showed highly significant evidence for association between rs1739843 and idiopathic DCM (p = 5.28 × 10?¹³, OR= 0.72 [95% CI 0.65-0.78]). None of the other three SNPs showed significant results in the replication stage.This finding of the HSPB7 gene from a genetic search for idiopathic DCM using a large SNP panel underscores the influence of common polymorphisms on DCM susceptibility.

Project description:BackgroundThe genetic factors and pathogenesis of idiopathic dilated cardiomyopathy-induced heart failure (IDCM-HF) have not been understood thoroughly; there is a lack of specific diagnostic markers and treatment methods for the disease. Hence, we aimed to identify the mechanisms of action at the molecular level and potential molecular markers for this disease.MethodsGene expression profiles of IDCM-HF and non-heart failure (NF) specimens were acquired from the database of Gene Expression Omnibus (GEO). We then identified the differentially expressed genes (DEGs) and analyzed their functions and related pathways by using "Metascape". Weighted gene co-expression network analysis (WGCNA) was utilized to search for key module genes. Candidate genes were identified by intersecting the key module genes identified via WGCNA with DEGs and further screened via the support vector machine-recursive feature elimination (SVM-RFE) method and the least absolute shrinkage and selection operator (LASSO) algorithm. At last, the biomarkers were validated and evaluated the diagnostic efficacy by the area under curve (AUC) value and further confirmed the differential expression in the IDCM-HF and NF groups using an external database.ResultsWe detected 490 genes exhibiting differential expression between IDCM-HF and NF specimens from the GSE57338 dataset, with most of them being concentrated in the extracellular matrix (ECM) of cells related to biological processes and pathways. After screening, 13 candidate genes were identified. Aquaporin 3 (AQP3) and cytochrome P450 2J2 (CYP2J2) showed high diagnostic efficacy in the GSE57338 and GSE6406 datasets, respectively. In comparison to the NF group, AQP3 was significantly down-regulated in the IDCM-HF group, while CYP2J2 was significantly up-regulated.ConclusionAs far as we know, this is the first study that combines WGCNA and machine learning algorithms to screen for potential biomarkers of IDCM-HF. Our findings suggest that AQP3 and CYP2J2 could be used as novel diagnostic markers and treatment targets of IDCM-HF.

Dataset Information

A genetic association study of heart failure: more evidence for the role of BAG3 in idiopathic dilated cardiomyopathy.

Aims

Methods and results

Conclusions

Publications

A genetic association study of heart failure: more evidence for the role of BAG3 in idiopathic dilated cardiomyopathy.

Similar Datasets

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