title: 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.
authors.affiliation: Department of Electrophysiology, Heart Center Leipzig, Leipzig University, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Husser
authors.affiliation: Department of Electrophysiology, Heart Center Leipzig, Leipzig University, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Ueberham
authors.affiliation: Department of Electrophysiology, Heart Center Leipzig, Leipzig University, Germany.
authors.forename: Borislav
authors.initials: B
authors.lastname: Dinov
authors.affiliation: Department of Electrophysiology, Heart Center Leipzig, Leipzig University, Germany.
authors.forename: Jedrzej
authors.initials: J
authors.lastname: Kosiuk
authors.affiliation: Department of Electrophysiology, Heart Center Leipzig, Leipzig University, Germany.
authors.forename: Jelena
authors.initials: J
authors.lastname: Kornej
authors.affiliation: Department of Electrophysiology, Heart Center Leipzig, Leipzig University, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Hindricks
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, TN, USA.
authors.forename: M Benjamin
authors.initials: MB
authors.lastname: Shoemaker
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, TN, USA.
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
authors.affiliation: Department of Electrophysiology, Heart Center Leipzig, Leipzig University, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bollmann
authors.affiliation: Department of Electrophysiology, Heart Center Leipzig, Leipzig University, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Büttner
mesh_terms: D000368:Aged; D001281:Atrial Fibrillation / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D020013:Calcium Signaling; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide