Dataset Information

Genomic contributors to atrial electroanatomical remodeling and atrial fibrillation progression: Pathway enrichment analysis of GWAS data.

ABSTRACT: In atrial fibrillation (AF), left atrial diameter (LAD) and low voltage area (LVA) are intermediate phenotypes that are associated with AF type and progression. In this study, we tested the hypothesis, that these phenotypes share common, genetically-determined pathways using pathway enrichment analysis of GWAS data. Samples from 660 patients with paroxysmal (n?=?370) or persistent AF (n?=?290) were genotyped for ~1,000,000 SNPs. SNPs found significantly associated with LAD, LVA or AF type were used for gene-based association tests in a systematic biological Knowledge-based mining system for Genome-wide Genetic studies (KGG). Associated genes were tested for pathway enrichment using two enrichment tools (WebGestalt and GATHER) and the databases provided by Kyoto Encyclopedia of Genes and Genomes. The calcium signaling pathway (hsa04020) was the only pathway that reached statistical significance for LAD and LVA in both enrichment tools and was also significantly associated with AF type. Within this pathway, there were 39 genes (i.e. CACNA1C, RyR2) that were associated with LAD, LVA and AF type. In conclusion, there is a genomic contribution to electroanatomical remodeling (LAD, LVA) and AF type via the calcium signaling pathway. Future and larger studies are necessary to replicate and apply these findings.

SUBMITTER: Husser D

PROVIDER: S-EPMC5114680 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Genomic contributors to atrial electroanatomical remodeling and atrial fibrillation progression: Pathway enrichment analysis of GWAS data.

Husser Daniela D Ueberham Laura L Dinov Borislav B Kosiuk Jedrzej J Kornej Jelena J Hindricks Gerhard G Shoemaker M Benjamin MB Roden Dan M DM Bollmann Andreas A Büttner Petra P

Scientific reports 20161118

In atrial fibrillation (AF), left atrial diameter (LAD) and low voltage area (LVA) are intermediate phenotypes that are associated with AF type and progression. In this study, we tested the hypothesis, that these phenotypes share common, genetically-determined pathways using pathway enrichment analysis of GWAS data. Samples from 660 patients with paroxysmal (n = 370) or persistent AF (n = 290) were genotyped for ~1,000,000 SNPs. SNPs found significantly associated with LAD, LVA or AF type were u ...[more]

PMID: 27857207

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Project description:Left atrial enlargement and persistent atrial fibrillation (AF) are well-known predictors for arrhythmia recurrence after AF catheter ablation (LRAF). In this study, by using pathway enrichment analysis of GWAS data, we tested the hypothesis that genetic pathways associated with these phenotypes are also associated with LRAF.Samples from 660 patients with paroxysmal (n = 370) or persistent AF (n = 290) undergoing de-novo AF catheter ablation were genotyped for ~1,000,000 SNPs. SNPs found to be significantly associated with left atrial diameter (LAD) or AF type were used for gene-based association tests in a systematic biological Knowledge-based mining system for Genome-wide Genetic studies (KGG). Associated genes were tested for pathway enrichment using WEB-based Gene SeT AnaLysis Toolkit (WebGestalt), the Gene Annotation Tool to Help Explain Relationships (GATHER) and the databases provided by Kyoto Encyclopedia of Genes and Genomes (KEGG). In a second step, the association of consistently enriched pathways and LRAF was tested.By using sequential 7-day Holter ECGs, LRAF between 3 and 12 months was observed in 48% and was associated with LAD (B = 1.801, 95% CI 0.760-2.841, p = 1.0E-3) and persistent AF (OR = 2.1; 95% CI 1.567-2.931, p = 2.0E-6). WebGestalt (adj. p = 2.7E-22) and GATHER (adj. p = 5.2E-3) identified the calcium signaling pathway (hsa04020) as the only consistently enriched pathway for LAD, while the extracellular matrix (ECM) -receptor interaction pathway (hsa04512) was the only consistently enriched pathway for AF type (adj. p = 2.1E-15 in WebGestalt; adj. p = 9.3E-4 in GATHER). Both calcium signaling (adj. p = 2.2E-17 in WebGestalt; adj. p = 2.9E-2 in GATHER) and ECM-receptor interaction (adj. p = 1.2E-10 in WebGestalt; adj. p = 2.9E-2 in GATHER) were significantly associated with LRAF.Calcium signaling and ECM-receptor interaction pathways are associated with LAD and AF type and, in turn, with LRAF. Future and larger studies are necessary to replicate and apply these findings.

Project description:Background Enlargement of left atrial ( LA ) size indicates advanced disease stage in patients with atrial fibrillation ( AF ) and is associated with poor success of different AF therapies. Two dimensional echocardiographic LA measurements do not reliably reflect the true size of LA anatomy. The aim of the current study was: 1) to analyze cardiovascular magnetic resonance ( CMR )-derived LA dimensions and their association with low voltage areas ( LVA ); and 2) to investigate the association between these parameters and NT -pro ANP (N-terminal proatrial natriuretic peptide) levels. Methods and Results Patients undergoing first AF catheter ablation were included. All patients underwent CMR imaging (Ingenia 1.5T Philips) before intervention. CMR data ( LA volume, superior-inferior, transversal and anterior-posterior LA diameters) were measured in all patients. LVA were determined using high-density maps and a low voltage threshold <0.5 mV. Blood plasma samples from femoral vein were collected before catheter ablation. NT -pro ANP levels were studied using commercially available assays. There were 216 patients (65±11 years, 59% males, 56% persistent AF , 26% LVA ) included into analyses. NT -pro ANP levels in patients with LVA were significantly higher than in those without (median/interquartile range 22 [13-29] versus 15 [9-22] pg/mL, P=0.004). All CMR derived LA diameters correlated significantly with persistent AF ( r²=0.291-0.468, all P<0.001), LVA ( r²=0.187-0.306, all P<0.001), and NT -pro ANP levels ( r²=0.258-0.352, P<0.01). On logistic regression multivariable analysis, age (odds ratio=1.090, 95% confidence interval: 1.030-1.153, P=0.003), females (odds ratio=2.686, 95% confidence interval: 1.047-6.891, P=0.040), and LA volume (odds ratio=1.022, 95% confidence interval: 1.009-1.035, P=0.001) remained significant predictors for LVA . Conclusions Left atrial CMR parameters are associated with persistent AF , low voltage areas and NT -pro ANP levels. LA volume is the most significant predictor for LVA .

Dataset Information

Genomic contributors to atrial electroanatomical remodeling and atrial fibrillation progression: Pathway enrichment analysis of GWAS data.

Publications

Genomic contributors to atrial electroanatomical remodeling and atrial fibrillation progression: Pathway enrichment analysis of GWAS data.

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