Genomic Contributors to Rhythm Outcome of Atrial Fibrillation Catheter Ablation – Pathway Enrichment Analysis of GWAS Data

Abstract

BackgroundLeft 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.MethodsSamples 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.ResultsBy 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.ConclusionsCalcium 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.

Identification of Central Regulators of Calcium Signaling and ECM–Receptor Interaction Genetically Associated With the Progression and Recurrence of Atrial Fibrillation

“…This study was based on recently published findings ( Husser et al, 2016a ). Patient characteristics, clinical parameters, genome-wide association analysis, gene-based association testing, pathway analysis, and gene lists can be found in Supplementary Methods and Supplementary Table S1 .…”

“…Common genetic variants contribute to the progression and recurrence of atrial fibrillation (AF; Olesen et al, 2014 ). We recently used genome-wide association study data from 660 AF patients to detect common variants that associate with left atrial diameter, AF type (paroxysmal vs. persistent AF), and AF recurrence ( Husser et al, 2016a , b ). Based on the hypothesis that all genetic variants irrespective of their significance level contribute to genetic background, we included all variants with p < 0.05 in our analysis irrespective if they were coding, non-coding, synonymous, or non-synonymous.…”

“…Using a stepwise filtering procedure, we shifted the conventional SNP-based analysis toward a gene-based analysis ( Li et al, 2011 ; Chanda et al, 2013 ) and finally tested the genes for non-random enrichment in physiological pathways. This approach revealed an association of calcium signaling (55 genes) and ECM–receptor interaction (26 genes) with left atrial diameter and AF type, respectively, and also with AF recurrence ( Husser et al, 2016a ; see Supplementary Table S1 ). Abnormal intracellular Ca(2+) load, distribution, and handling are involved in AF initiation, maintenance, and progression ( Nattel and Dobrev, 2012 ) as well as heterogeneous conduction slowing and reentry ( Yue et al, 2011 ).…”

PR Interval Associated Genes, Atrial Remodeling and Rhythm Outcome of Catheter Ablation of Atrial Fibrillation—A Gene-Based Analysis of GWAS Data

“…This study extends the concept of analyzing clinically-overlapping phenotypes with shared genotypes. By applying this, we were already able to identify genes of calcium signaling pathway ( SLC8A1 ) and the ECM receptor interaction pathway ( ITGA9 ) to associate with recurring AF (Husser et al, 2016a ).…”

Analysis of Genes Involved in Persistent Atrial Fibrillation: Comparisons of ‘Trigger’ and ‘Substrate’ Differences

“…Recently, Husser's group performed clinical and genetic predictor analysis based on pathway enrichment analysis of GWAS (Genome-wide Association Study) data, and demonstrated that the ECM-receptor interaction pathways were significantly associated with left atrial enlargement and AF type and response to AF catheter ablation [33]. Presumably, ECM remodeling revealed complex relationships between cell-to-cell interactions and communication, and was validated as a central mediator that tightly links ion channels with the development of an ectopic pacemaker [33]. Although the previous studies and our results have provided evidence to show that ECM interaction is a potential target, the precise molecular mechanisms of the ECM in the progressive nature of AF are still unknown.…”