Variants conferring risk of atrial fibrillation on chromosome 4q25

Guðbjartsson, Daníel F.; Arnar, Davíð O.; Helgadóttir, Anna; Grétarsdóttir, Sólveig; Hólm, Hilma; Sigurðsson, Ásgeir; Jónasdóttir, Aðalbjörg; Baker, Adam; Þorleifsson, Guðmar; Kristjánsson, Kristleifur; Pálsson, Arnar; Blöndal, Thórarinn; Sulem, Patrick; Backman, Valgerdur M; Hardarson, Gudmundur A.; Pálsdóttir, Ebba; Helgason, Agnar; Sigurjónsdóttir, Rúna; Sverrisson, Jon Th.; Kostulas, Konstantinos; Ng, Maggie C. Y.; Baum, Larry; So, Wing Yee; Wong, Ka Sing; Chan, Juliana C.N.; Furie, Karen L.; Greenberg, Steven M.; Sale, Michelle; Kelly, Peter; MacRae, Calum A.; Smith, Eric E.; Rosand, Jonathan; Hillert, Jan; Ronald, C.; Ellinor, Patrick T.; Þorgeirsson, Guðmundur; Gulcher, Jeffrey R.; Kong, Augustine; Þorsteinsdóttir, Unnur; Stefánsson, Kāri

doi:10.1038/nature06007

Cited by 828 publications

(756 citation statements)

References 23 publications

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“…24 Therefore, population-based or genome-wide studies have been used to identify many AF risk loci. 25,26,27,28,29,30 The genes at these loci encode transcription factors and ion channels, and many are without a clear relation to AF at the present time.…”

Section: Section 2: Definitions Mechanisms and Rationale For Af Ablmentioning

confidence: 99%

2012 HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation: Recommendations for Patient Selection, Procedural Techniques, Patient Management and Follow-up, Definitions, Endpoints, and Research Trial Design

Calkins,

Kuck,

Cappato

et al. 2012

Heart Rhythm

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Section: Section 2: Definitions Mechanisms and Rationale For Af Ablmentioning

confidence: 99%

2012 HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation: Recommendations for Patient Selection, Procedural Techniques, Patient Management and Follow-up, Definitions, Endpoints, and Research Trial Design

Calkins,

Kuck,

Cappato

et al. 2012

Heart Rhythm

1,748

1,450

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“…Recently, GWA studies have been used to investigate common and complex traits such as coronary artery disease [65,66], atrial fibrillation [67], prolonged QT interval, and SCD [68,69]. Following on from the discovery that common polymorphisms in the 5′ regulatory region of NOS1AP, encoding the protein Capon, modulate QTc, investigators are now examining the role of this set of variants in mediating SCD susceptibility in the NHLBI's ARIC (athereoscelerosis risk in communities) and CHS (cardiovascular health study-total enrollment >20,000), longitudinal studies.…”

Section: Current and Future Directionsmentioning

confidence: 99%

Genomics, heart failure and sudden cardiac death

Darbar

2008

Heart Fail Rev

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Sudden cardiac death (SCD) is among the most common causes of death in developed countries throughout the world. Despite decreased overall cardiac mortality, SCD vrates appear to be increasing in concert with escalating global prevalence of coronary disease and heart failure, the two major conditions predisposing to SCD. This unfavorable trend is a consequence of our inability to identify those who will die suddenly from lethal ventricular arrhythmias and to develop effective therapies for all populations at risk. The known risk factors for SCD lack the predictive power needed to generate preventive strategies for the large number of fatal arrhythmic events that occur among lowerrisk subsets of the population. Even among recognized high-risk subsets, prediction of SCD remains challenging. With the exception of the implantable cardioverter defibrillator (ICD) there are few effective strategies for the prevention and treatment of SCD. This article discusses the prospect of genomic science as an approach to the identification of patients at high-risk for SCD. While the final common pathway for SCD is malignant ventricular arrhythmias, there are many potential contributors, pathways, and mechanisms by which common genetic variants (polymorphisms) could affect initiation and propagation of life-threatening cardiac arrhythmias. Recent advances in genomic medicine now provide us with novel approaches to both identify candidate genes/pathways and relatively common polymorphisms which may predispose patients to increased risk for SCD. Improved understanding of the relationship between common polymorphisms and SCD will not only improve risk stratification such that ICDs can be targeted to those patients most likely to benefit from them but also provide new insight into the pathophysiology of SCD. KeywordsSudden cardiac death; Genomics; Heart failure; Single nucleotide polymorphisms Heart failure and SCD Heart failure (HF) afflicts approximately 5 million people in the United States, with 550,000 new cases reported annually, but as the population ages both the incidence and prevalence is expected to rise [1]. HF is associated with high mortality and is reportedly responsible for 300,000 deaths annually in the US [1]. Prior to advent of neuro-hormonal antagonists, the mean duration of survival after onset of HF was 1.7 years for men and 3.2 years for women, with only half of patients still alive after 5 years of onset [2]. The two modes of death in patients with HF are circulatory failure due to progressive left ventricular (LV) dysfunction associated with gradual worsening of symptoms, or sudden cardiac death (SCD) in relatively clinically stable patients [3].Although the proportion of sudden deaths in published trials varies significantly, probably due to varying interpretations of reported modes of death, clinical trials data suggests that SCD accounts for approximately one-third of all HF deaths [4]. Epidemiologic evidence from the Framingham heart study suggests that about one-half of all deaths due to HF occur...

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“…In addition, inheritable defects also confer substantial disease susceptibility on patients with secondary AF. 25 Nevertheless, AF is a genetically heterogeneous disorder, and genetic defects in a significant proportion of AF patients remain to be identified. 26 In this study, we describe the identification and characterization of novel KCNA5 mutations as genetic determinants for AF.…”

Section: Introductionmentioning

confidence: 99%

Novel KCNA5 loss-of-function mutations responsible for atrial fibrillation

et al. 2009

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Accumulating evidence reveals that genetic variants play pivotal roles in familial atrial fibrillation (AF). However, the molecular defects in most patients with AF remain to be identified. Here, we report on three novel KCNA5 mutations that were identified in 4 of 120 unrelated AF families. Among them, T527M was found in two AF families, and A576V and E610K in two other AF families, respectively. The mutations T527M and A576V were also detected in 2 and 1 of 256 patients with idiopathic AF, respectively. The same mutations were not observed in 200 secondary AF patients and 500 controls. Functional analyses revealed consistent loss-of-function effects of mutant KCNA5 proteins on the ultrarapidly activating delayed rectifier potassium currents. These findings expand the spectrum of mutations in KCNA5 linked to AF and provide new insight into the molecular mechanism involved in AF.

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Variants conferring risk of atrial fibrillation on chromosome 4q25

Cited by 828 publications

References 23 publications

2012 HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation: Recommendations for Patient Selection, Procedural Techniques, Patient Management and Follow-up, Definitions, Endpoints, and Research Trial Design

2012 HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation: Recommendations for Patient Selection, Procedural Techniques, Patient Management and Follow-up, Definitions, Endpoints, and Research Trial Design

Genomics, heart failure and sudden cardiac death

Novel KCNA5 loss-of-function mutations responsible for atrial fibrillation

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