心房颤动导管消融节律结果的基因组贡献者——全基因组关联研究（GWAS）数据的通路富集分析
Genomic Contributors to Rhythm Outcome of Atrial Fibrillation Catheter Ablation - Pathway Enrichment Analysis of GWAS Data.
作者信息
Husser Daniela, Büttner Petra, Ueberham Laura, Dinov Borislav, Sommer Philipp, Arya Arash, Hindricks Gerhard, Bollmann Andreas
机构信息
Department of Electrophysiology, Heart Center Leipzig, Leipzig University, Leipzig, Germany.
出版信息
PLoS One. 2016 Nov 21;11(11):e0167008. doi: 10.1371/journal.pone.0167008. eCollection 2016.
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
背景
左心房扩大和持续性心房颤动（AF）是AF导管消融（LRAF）后心律失常复发的众所周知的预测因素。在本研究中，通过对全基因组关联研究（GWAS）数据进行通路富集分析，我们检验了与这些表型相关的遗传通路也与LRAF相关的假设。
方法
对660例接受初次AF导管消融的阵发性（n = 370）或持续性AF（n = 290）患者的样本进行约100万个单核苷酸多态性（SNP）基因分型。在基于系统生物学知识的全基因组遗传研究挖掘系统（KGG）中，将发现与左心房直径（LAD）或AF类型显著相关的SNP用于基于基因的关联测试。使用基于网络的基因集分析工具包（WebGestalt）、帮助解释关系的基因注释工具（GATHER）以及京都基因与基因组百科全书（KEGG）提供的数据库，对相关基因进行通路富集测试。第二步，测试持续富集的通路与LRAF之间的关联。
结果
通过连续7天的动态心电图监测，3至12个月内观察到LRAF的发生率为48%，且与LAD（B = 1.801，95%置信区间0.760 - 2.841，p = 1.0×10⁻³）和持续性AF（OR = 2.1；95%置信区间1.567 - 2.931，p = 2.0×10⁻⁶）相关。WebGestalt（校正p = 2.7×10⁻²²）和GATHER（校正p = 5.2×10⁻³）将钙信号通路（hsa04020）确定为LAD唯一持续富集的通路，而细胞外基质（ECM）-受体相互作用通路（hsa04512）是AF类型唯一持续富集的通路（WebGestalt校正p = 2.1×10⁻¹⁵；GATHER校正p = 9.3×10⁻⁴）。钙信号通路（WebGestalt校正p = 2.2×10⁻¹⁷；GATHER校正p = 2.9×10⁻²）和ECM-受体相互作用通路（WebGestalt校正p = 1.2×10⁻¹⁰；GATHER校正p = 2.9×10⁻²）均与LRAF显著相关。
结论
钙信号通路和ECM-受体相互作用通路与LAD和AF类型相关，进而与LRAF相关。未来需要进行更大规模的研究来重复和应用这些发现。
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