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Canadian Journal of Cardiology

Atrial Fibrillation Genetics: Is There a Practical Clinical Value Now or in the Future?

Published:February 11, 2016DOI:https://doi.org/10.1016/j.cjca.2016.02.032

      Abstract

      Atrial fibrillation (AF) is the most common sustained arrhythmia and has significant clinical impact. Over the last decade, our understanding of the genetics of AF has expanded dramatically. After a heritable predisposition for AF was identified, many investigators have in turn identified both common and rare variants associated with AF. Ongoing work is focused on translating these variants into disease pathways and novel therapeutic modalities. In this review, we focus on our understanding of the current concepts behind the genetics of AF and outline a vision for the incorporation of genetic data into clinical practice.

      Résumé

      La fibrillation auriculaire (FA) est le type d’arythmie soutenue le plus fréquent et son incidence clinique est significative. Au cours de la dernière décennie, notre connaissance de la génétique de la FA a littéralement explosé. En effet, après avoir cerné une prédisposition génétique à la FA, de nombreux chercheurs ont découvert des variantes génétiques fréquentes et rares de la maladie. Des travaux sont en cours pour associer ces variantes à des voies pathogéniques particulières et ainsi établir de nouvelles modalités thérapeutiques. Ce tour d’horizon est axé sur notre compréhension actuelle de la génétique de la FA et sur les façons d’incorporer les données génétiques dans la pratique clinique.
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      References

        • Kannel W.B.
        • Benjamin E.J.
        Status of the epidemiology of atrial fibrillation.
        Med Clin North Am. 2008; 92 (ix): 17-40
        • Schnabel R.B.
        • Sullivan L.M.
        • Levy D.
        • et al.
        Development of a risk score for atrial fibrillation (Framingham Heart Study): a community-based cohort study.
        Lancet. 2009; 373: 739-745
        • Everett B.M.
        • Cook N.R.
        • Conen D.
        • et al.
        Novel genetic markers improve measures of atrial fibrillation risk prediction.
        Eur Heart J. 2013; 34: 2243-2251
        • Wolff L.
        Familial auricular fibrillation.
        NEngl.J Med. 1943; 229: 396-398
        • Fox C.S.
        • Parise H.
        • D'Agostino Sr., R.B.
        • et al.
        Parental atrial fibrillation as a risk factor for atrial fibrillation in offspring.
        JAMA. 2004; 291: 2851-2855
        • Lubitz S.A.
        • Yin X.
        • Fontes J.D.
        • et al.
        Association between familial atrial fibrillation and risk of new-onset atrial fibrillation.
        JAMA. 2010; 304: 2263-2269
        • Arnar D.O.
        • Holm H.
        • Gudbjartsson D.F.
        Predicting atrial fibrillation.
        Lancet. 2009; 373: 1523-1524
        • Christophersen I.E.
        • Budtz-Jorgensen E.
        • Olesen M.S.
        • et al.
        Familial atrial fibrillation predicts increased risk of mortality: a study in Danish twins.
        Circ Arrhythm Electrophysiol. 2013; 6: 10-15
        • Darbar D.
        • Herron K.J.
        • Ballew J.D.
        • et al.
        Familial atrial fibrillation is a genetically heterogeneous disorder.
        J Am Coll Cardiol. 2003; 41: 2185-2192
        • Ellinor P.T.
        • Yoerger D.M.
        • Ruskin J.N.
        • MacRae C.A.
        Familial aggregation in lone atrial fibrillation.
        Hum Genet. 2005; 118: 179-184
        • Oyen N.
        • Ranthe M.F.
        • Carstensen L.
        • et al.
        Familial aggregation of lone atrial fibrillation in young persons.
        J Am Coll Cardiol. 2012; 60: 917-921
        • Chen Y.H.
        • Xu S.J.
        • Bendahhou S.
        • et al.
        KCNQ1 gain-of-function mutation in familial atrial fibrillation.
        Science. 2003; 299: 251-254
        • Wirka R.C.
        • Gore S.
        • Van Wagoner D.R.
        • et al.
        A common connexin-40 gene promoter variant affects connexin-40 expression in human atria and is associated with atrial fibrillation.
        Circ Arrhythm Electrophysiol. 2011; 4: 87-93
        • Olesen M.S.
        • Jespersen T.
        • Nielsen J.B.
        • et al.
        Mutations in sodium channel beta-subunit SCN3B are associated with early-onset lone atrial fibrillation.
        Cardiovasc Res. 2011; 89: 786-793
        • Olesen M.S.
        • Refsgaard L.
        • Holst A.G.
        • et al.
        A novel KCND3 gain-of-function mutation associated with early-onset of persistent lone atrial fibrillation.
        Cardiovasc Res. 2013; 98: 488-495
        • Wang J.
        • Zhang D.F.
        • Sun Y.M.
        • Yang Y.Q.
        A novel PITX2c loss-of-function mutation associated with familial atrial fibrillation.
        Eur J Med Genet. 2014; 57: 25-31
        • Yu H.
        • Xu J.H.
        • Song H.M.
        • et al.
        Mutational spectrum of the NKX2-5 gene in patients with lone atrial fibrillation.
        Int Med Sci. 2014; 11: 554-563
        • Jiang J.Q.
        • Shen F.F.
        • Fang W.Y.
        • Liu X.
        • Yang Y.Q.
        Novel GATA4 mutations in lone atrial fibrillation.
        Int J Mol Med. 2011; 28: 1025-1032
        • Lubitz S.A.
        • Ellinor P.T.
        A common connexion between gap junctions, single nucleotide polymorphisms, and atrial fibrillation?.
        Can J Cardiol. 2013; 29: 3-5
        • Christophersen I.E.
        • Holmegard H.N.
        • Jabbari J.
        • et al.
        Rare variants in GJA5 are associated with early-onset lone atrial fibrillation.
        Can J Cardiol. 2013; 29: 111-116
        • Olesen M.S.
        • Andreasen L.
        • Jabbari J.
        • et al.
        Very early-onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation.
        Heart Rhythm. 2014; 11: 246-251
        • Gudbjartsson D.F.
        • Arnar D.O.
        • Helgadottir A.
        • et al.
        Variants conferring risk of atrial fibrillation on chromosome 4q25.
        Nature. 2007; 448: 353-357
        • Mommersteeg M.T.
        • Brown N.A.
        • Prall O.W.
        • et al.
        Pitx2c and Nkx2-5 are required for the formation and identity of the pulmonary myocardium.
        Circ Res. 2007; 101: 902-909
        • Mommersteeg M.T.
        • Hoogaars W.M.
        • Prall O.W.
        • et al.
        Molecular pathway for the localized formation of the sinoatrial node.
        Circ Res. 2007; 100: 354-362
        • Wang J.
        • Klysik E.
        • Sood S.
        • Johnson R.L.
        • Wehrens X.H.
        • Martin J.F.
        Pitx2 prevents susceptibility to atrial arrhythmias by inhibiting left-sided pacemaker specification.
        Proc Natl Acad Sci USA. 2010; 107: 9753-9758
        • Lubitz S.A.
        • Sinner M.F.
        • Lunetta K.L.
        • et al.
        Independent susceptibility markers for atrial fibrillation on chromosome 4q25.
        Circulation. 2010; 122: 976-984
        • Ritchie M.D.
        • Rowan S.
        • Kucera G.
        • et al.
        Chromosome 4q25 variants are genetic modifiers of rare ion channel mutations associated with familial atrial fibrillation.
        J Am Coll Cardiol. 2012; 60: 1173-1181
        • Wang J.
        • Bai Y.
        • Li N.
        • et al.
        Pitx2-microRNA pathway that delimits sinoatrial node development and inhibits predisposition to atrial fibrillation.
        Proc Natl Acad Sci USA. 2014; 111: 9181-9186
        • Ellinor P.T.
        • Lunetta K.L.
        • Glazer N.L.
        • et al.
        Common variants in KCNN3 are associated with lone atrial fibrillation.
        Nat Genet. 2010; 42: 240-244
        • Kohler M.
        • Hirschberg B.
        • Bond C.T.
        • et al.
        Small-conductance, calcium-activated potassium channels from mammalian brain.
        Science. 1996; 273: 1709-1714
        • Zhang Z.
        • He Y.
        • Tuteja D.
        • et al.
        Functional roles of Cav1.3(alpha1D) calcium channels in atria: insights gained from gene-targeted null mutant mice.
        Circulation. 2005; 112: 1936-1944
        • Li N.
        • Timofeyev V.
        • Tuteja D.
        • et al.
        Ablation of a Ca2+-activated K+ channel (SK2 channel) results in action potential prolongation in atrial myocytes and atrial fibrillation.
        J.Physiol. 2009; 587: 1087-1100
        • Ozgen N.
        • Dun W.
        • Sosunov E.A.
        • et al.
        Early electrical remodeling in rabbit pulmonary vein results from trafficking of intracellular SK2 channels to membrane sites.
        Cardiovasc Res. 2007; 75: 758-769
        • Hsueh C.H.
        • Chang P.C.
        • Hsieh Y.C.
        • et al.
        Proarrhythmic effect of blocking the small conductance calcium activated potassium channel in isolated canine left atrium.
        Heart Rhythm. 2013; 10: 891-898
        • Ellinor P.T.
        • Lunetta K.L.
        • Albert C.M.
        • et al.
        Meta-analysis identifies six new susceptibility loci for atrial fibrillation.
        Nat Genet. 2012; 44: 670-675
        • Sinner M.F.
        • Tucker N.R.
        • Lunetta K.L.
        • et al.
        Integrating genetic, transcriptional, and functional analyses to identify five novel genes for atrial fibrillation.
        Circulation. 2014; 130: 1225-1235
        • January C.T.
        • Wann L.S.
        • Alpert J.S.
        • et al.
        AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society.
        J Am Coll Cardiol. 2014; 64: e1-e76
        • Benjamin E.J.
        • Levy D.
        • Vaziri S.M.
        • et al.
        Independent risk factors for atrial fibrillation in a population-based cohort. The Framingham Heart Study.
        JAMA. 1994; 271: 840-844
        • Psaty B.M.
        • Manolio T.A.
        • Kuller L.H.
        • et al.
        Incidence of and risk factors for atrial fibrillation in older adults.
        Circulation. 1997; 96: 2455-2461
        • Alonso A.
        • Krijthe B.P.
        • Aspelund T.
        • et al.
        Simple risk model predicts incidence of atrial fibrillation in a racially and geographically diverse population: the CHARGE-AF consortium.
        J Am Heart Assoc. 2013; 2: e000102
        • Lubitz S.A.
        • Lunetta K.L.
        • Lin H.
        • et al.
        Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese.
        J Am Coll Cardiol. 2014; 63: 1200-1210
        • Parvez B.
        • Benjamin Shoemaker M.
        • Muhammad R.
        • et al.
        Common genetic polymorphism at 4q25 locus predicts atrial fibrillation recurrence after successful cardioversion.
        Heart Rhythm. 2013; 10: 849-855
        • Benjamin Shoemaker M.
        • Muhammad R.
        • Parvez B.
        • et al.
        Common atrial fibrillation risk alleles at 4q25 predict recurrence after catheter-based atrial fibrillation ablation.
        Heart Rhythm. 2013; 10: 394-400
        • Husser D.
        • Adams V.
        • Piorkowski C.
        • Hindricks G.
        • Bollmann A.
        Chromosome 4q25 variants and atrial fibrillation recurrence after catheter ablation.
        J Am Coll Cardiol. 2010; 55: 747-753
        • Parvez B.
        • Vaglio J.
        • Rowan S.
        • et al.
        Symptomatic response to antiarrhythmic drug therapy is modulated by a common single nucleotide polymorphism in atrial fibrillation.
        J Am Coll Cardiol. 2012; 60: 539-545
        • Gretarsdottir S.
        • Thorleifsson G.
        • Manolescu A.
        • et al.
        Risk variants for atrial fibrillation on chromosome 4q25 associate with ischemic stroke.
        Ann Neurol. 2008; 64: 402-409
        • Lemmens R.
        • Buysschaert I.
        • Geelen V.
        • et al.
        The association of the 4q25 susceptibility variant for atrial fibrillation with stroke is limited to stroke of cardioembolic etiology.
        Stroke. 2010; 41: 1850-1857
        • Lahtinen A.M.
        • Noseworthy P.A.
        • Havulinna A.S.
        • et al.
        Common genetic variants associated with sudden cardiac death: the FinSCDgen study.
        PLoS One. 2012; 7: e41675
        • Virani S.S.
        • Brautbar A.
        • Lee V.V.
        • et al.
        Usefulness of single nucleotide polymorphism in chromosome 4q25 to predict in-hospital and long-term development of atrial fibrillation and survival in patients undergoing coronary artery bypass grafting.
        Am J Cardiol. 2011; 107: 1504-1509
        • Body S.C.
        • Collard C.D.
        • Shernan S.K.
        • et al.
        Variation in the 4q25 chromosomal locus predicts atrial fibrillation after coronary artery bypass graft surgery.
        Circ Cardiovasc Genet. 2009; 2: 499-506
        • Shoemaker M.B.
        • Bollmann A.
        • Lubitz S.A.
        • et al.
        Common genetic variants and response to atrial fibrillation ablation.
        Circ Arrhythm Electrophysiol. 2015; 8: 296-302
        • Choi E.K.
        • Park J.H.
        • Lee J.Y.
        • et al.
        Korean atrial fibrillation (AF) network: genetic variants for AF do not predict ablation success.
        J Am Heart Assoc. 2015; 4: e002046
        • Odum L.E.
        • Cochran K.A.
        • Aistrope D.S.
        • Snella K.A.
        The CHADS(2)versus the new CHA2DS2-VASc scoring systems for guiding antithrombotic treatment of patients with atrial fibrillation: review of the literature and recommendations for use.
        Pharmacotherapy. 2012; 32: 285-296
        • Gudbjartsson D.F.
        • Holm H.
        • Gretarsdottir S.
        • et al.
        A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke.
        Nat Genet. 2009; 41: 876-878
        • Whang W.
        • Davidson K.W.
        • Conen D.
        • et al.
        Global psychological distress and risk of atrial fibrillation among women: the Women's Health Study.
        J Am Heart Assoc. 2012; 1: e001107
        • Tada H.
        • Shiffman D.
        • Smith J.G.
        • et al.
        Twelve-single nucleotide polymorphism genetic risk score identifies individuals at increased risk for future atrial fibrillation and stroke.
        Stroke. 2014; 45: 2856-2862
        • Roberts J.D.
        • Gollob M.H.
        Impact of genetic discoveries on the classification of lone atrial fibrillation.
        J Am Coll Cardiol. 2010; 55: 705-712
        • Roberts J.D.
        • Gollob M.H.
        A contemporary review on the genetic basis of atrial fibrillation.
        Methodist Debakey Cardiovasc J. 2014; 10: 18-24