REVIEW URRENT C OPINION
Genetic basis of atrial fibrillation Kui Hong a,b and Qinmei Xiong a
Purpose of review Atrial fibrillation, the most common cardiac supraventricular arrhythmia, affects more than 5 million people worldwide. Increasing evidence has demonstrated that genetic factors play an important role in the pathogenesis of atrial fibrillation, and multiple genes responsible for atrial fibrillation have been identified. This review will focus on the recent findings in atrial fibrillation genetic studies and discuss the clinical implications of exploring the atrial fibrillation genetic basis. Recent findings The advent of the candidate gene approach and genome-wide association studies has facilitated the process of investigating the complex genetic background underlying the pathogenesis of atrial fibrillation. Recent genetic investigations have offered further insights into the predisposing genes encoding ion channels, connexin, atrial natriuretic peptide, RyR2, T-box transcription factor, nucleoporins and zinc-finger transcription factor. Common single-nucleotide polymorphisms are important factors in the development of lone atrial fibrillation, recurrent atrial fibrillation or atrial fibrillation complicated with cardiac disorders. Summary Analyses of candidate genes have revealed a growing number of atrial fibrillation-related genes. A better understanding of the genetic mechanism underlying atrial fibrillation would be expected to lead to more accurate risk stratification of atrial fibrillation and the discovery of optimal clinical treatment strategies that carry maximal efficacy and minimal risk in a manner that is consistent with the vision of pharmacogenomics. Keywords atrial fibrillation, gene, genetic testing
INTRODUCTION The prevalence of atrial fibrillation increases markedly with age, ranging from approximately 1% in the general population to approximately 10% in those aged over 75 years [1]. With the accelerating aging population process and the improved survival of patients with other cardiovascular disorders, atrial fibrillation is estimated to increase five-fold in prevalence by 2050 [2]. The presence of atrial fibrillation can cause serious complications and can independently increase the risk of mortality and morbidity. Atrial fibrillation confers a five-fold increase in the risk of stroke and approximately doubles mortality, resulting in a major financial burden to patients and healthcare systems. While the underlying mechanisms of atrial fibrillation are complex and not well understood, multiple potential pathways and risk factors have been investigated. Atrial fibrillation is generally known as a common complication in various cardiac and systemic disorders. Valvular heart disease, www.co-cardiology.com
hypertension, ischemic heart disease and hyperthyroidism are the most common causal risk factors. In some cases, atrial fibrillation can also exist in the absence of the previously mentioned predisposing factors and is defined as lone atrial fibrillation, of which up to 15% exhibits familial clustering. Since the first chromosomal locus was identified in 1997, a genetic susceptibility to the development of atrial fibrillation and emerging evidence has strongly implicated hereditary determinants for atrial fibrillation [3]. In this review article, we will focus on the recent findings in atrial fibrillation genetic studies a Cardiovascular Department and bThe Key Laboratory of Molecular Medicine, the Second Affiliated Hospital of Nanchang University, Nanchang, China
Correspondence to Kui Hong, MD, PhD, Cardiovascular Department, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Nanchang 330006, China. Tel: +86 791 86312917; e-mail: [email protected]. Curr Opin Cardiol 2014, 29:220–226 DOI:10.1097/HCO.0000000000000051 Volume 29 Number 3 May 2014
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Genetic basis of atrial fibrillation Hong and Xiong
KEY POINTS Since the first mutation gene KCNQ1 responsible for atrial fibrillation was identified in 2003, genetic studies have identified mutations associated with atrial fibrillation in at least 24 genes. Some SNPs are responsible for the risk of atrial fibrillation recurrence after pharmacological treatment, electrical cardioversion or catheter ablation. Routine genetic testing is not indicated for sporadic atrial fibrillation patients, based on limited currently available data.
and discuss the clinical implications of exploring the genetic basis of atrial fibrillation in this field.
some exceptional cases. The SCN5A mutation p.M1875T associated with familial atrial fibrillation displayed a gain-of-function type modulation of cardiac Naþ channels, which is a novel mechanism predisposing to increased atrial excitability and familial atrial fibrillation [9]. Mutations in KCNA5, encoding the ultra-rapid delayed rectifier potassium current (IKur), can result in a loss-of-function effect on IKur current and eventually lead to atrial fibrillation [21–23]. Mutations in the RYR2 gene contribute to abnormal Ca2þ handling in cardiomyocytes, which may produce various arrhythmias, including catecholaminergic polymorphic ventricular tachycardia (CPVT). Recent genetic findings have shown that p.S4153R mutation in RYR2 gene is a gain-of-function mutation associated with a clinical phenotype characterized by both CPVT and atrial fibrillation [29 ,30]. JPH2 is believed to play an important role in sarcoplasmic reticulum Ca2þ handling and modulation of RYR2. Beavers et al. [41 ] screened 203 unrelated hypertrophic cardiomyopathy patients and uncovered a novel JPH2 missense mutation, p.E169K, in two patients with juvenileonset paroxysmal atrial fibrillation. Further analysis suggested that JPH2-mediated destabilization of RYR2 due to a loss-of-function mutation can promote a sarcoplasmic reticulum Ca2þ leak and lead to CPVT and atrial fibrillation. These data may underscore the importance of Ca2þ dysregulation as a fundamental mechanism for both atrial and ventricular tachyarrhythmias, representing a potential novel therapeutic target for atrial fibrillation. Gap junctional proteins significantly mediate the electrical coupling of cardiomyocytes, which enables effective propagation of electrical activation and contraction of cardiomyocytes. Connexins are key members of gap junctional proteins, including connexin43 (Cx43) and connexin40 (Cx40), which are highly expressed in atrial tissues. Genetic studies have suggested that mutations in GJA1 and GJA5, the genes encoding Cx43 and Cx40, respectively, are also involved in the pathogenesis of atrial fibrilla¨ bkemeier et al. [47] generated tion [37–40]. Lu transgenic Cx40A96S mice as a model for atrial fibrillation and proposed the possibility of investigating the key effect of the GJA5 mutation in the etiopathology of certain cases of genetically mediated human atrial fibrillation. Recent findings may warrant a new investigation into several genes linked to the overlapping phenotype of congenital heart/skeletal defects and atrial fibrillation. Firstly, TBX5 is expressed in the embryonic heart and regulates transcription of downstream genes such as the atrial natriuretic &
GENE VARIANTS UNDERLYING ATRIAL FIBRILLATION In 1997, based on linkage analysis, 10q22-q24 as the genetic locus was identified in three families with autosomal dominant atrial fibrillation [3]. Although the exact genes responsible for atrial fibrillation in this region remain unknown, the scientific results instigated exploring the genetic characteristics of atrial fibrillation. Over the past decade, since the first mutation gene KCNQ1 responsible for atrial fibrillation was identified [4], genetic studies have identified mutations associated with atrial fibrillation in at least 25 genes: KCNQ1 [4–8], SCN5A [7,9–12], KCNH2 [13], KCNE2 [14], KCNE3 [15,16], KCNE5 [17], KCNJ2 [18–20], KCNA5 [7,21–23], ABCC9 [24], SCN1B [25], SCN2B [25], SCN3B [26,27], SCN4B [28 ], ryanodine receptor 2 (RYR2) [29 ,30,31], NKX2.5 [7,32], NPPA [7,33,34], T-box transcription factor 5 (TBX5) [35], NUP155 [36], GJA1 [37], GJA5 [38–40], Junctophilin 2 (JPH2) [41 ], PITX2c [42,43], GATA4 [44], GATA5 [45], and GATA6 [46] (Table 1). Mutations have also been identified in the patient population with atrial fibrillation complicated with other disorders. As exemplified by the findings of Hong et al. [5], a de-novo missense p.V141M mutation in KCNQ1 was identified in a baby girl who was diagnosed with atrial fibrillation with slow ventricular response and a short QT interval. Recent data have shown that almost all of the potassium channel and sodium channel genes are associated with the development of atrial fibrillation. Further functional analyses of the ion channel gene mutation have revealed that gain-of-function effects on potassium current and loss-of-function effects on sodium current can generally be responsible for the pathogenesis of atrial fibrillation, with &
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Molecular genetics Table 1. Gene mutations responsible for AF Gene KCNQ1
Genotype
Phenotype
Functional effect
References
Gain-of-function effect on Iks current
S140G
Familial AF
V141M
SQTS þ AF
Q147R
AF þ prolonged QT interval
Kv7.1 gain of function in the atria
Lundby et al., 2007 [6]
IAP54-56
Familial AF
Unknown
Ritchie et al., 2012 [7]
Chen et al., 2003 [4] Hong et al., 2005 [5]
R231C
AF þ LQT1
Gain-of-function effect on Iks current
Bartos et al., 2011 [8]
KCNH2
N588K
AF þ SQTS
Gain-of-function effect on Ikr current
Brugada et al., 2004 [13]
KCNE2
R27C
Familial AF
Gain-of-function effect on Ikr current
Yang et al., 2004 [14]
KCNE3
R53H
Familial AF
Unknown
Zhang et al., 2005 [15]
V17M
Early-onset lone AF
Gain-of-function effect on Ikr current
Lundby et al., 2008 [16]
L65F
AF þ ischemic heart disease þ mild hypertension
Gain-of-function effect on Iks current
Ravn et al., 2008 [17]
Gain-of-function effect on Ikr current
KCNE5 KCNJ2
KCNA5
G277A
AF
G514A
SQTS þ AF
E299V
PAF þ SQTS
T527M/A576V/E610K
Familial AF
E375X
Lone AF at age 35
71–81 del
Lone AF at age of 34
Xia et al., 2005 [18] Priori et al., 2005 [19] Deo et al., 2013 [20] Yang et al., 2009 [21]
Loss-of-function effect on Ikur currents
Olson et al., 2006 [22] Yang et al., 2010 [23] Ritchie et al., 2012 [7]
SCN5A
M1875T
Familial AF
Gain-of-function effect on INa current
Makiyama et al., 2008 [9]
D1275N
AF þ DCM
Loss-of-function effect on INa current
Olson et al., 2005 [10]
N1986K
Familial AF
Loss-of-function effect on INa current
Ellinor et al., 2008 [11]
T220I/R1897W/T1304M/ F1596I/R1626H/ D1819N/R340Q/V1951M
A cohort of patients with early-onset lone AF
Compromised transient peak current and increased sustained current
Olesen et al., 2012 [12]
A572D/E428K/H445D/ N470K/V1951M/L461V
Familial AF
Unknown
Ritchie et al., 2012 [7]
SCN1B
R85H/D153N
PAF and moderate aortic stenosis/lone PAF
Loss-of-function effect on INa current
Watanabe et al., 2009 [25]
SCN2B
R28Q/R28W
PAF and hypertension/PAF and hypertension
Loss-of-function effect on INa current
Watanabe et al., 2009 [25]
SCN3B
R6K/L10P/M161T
Early-onset lone AF
Loss of function in the sodium current
Olesen et al., 2011 [26]
A130V
Lone AF
Functional dominant-negative mutation
Wang et al., 2010 [27]
SCN4B
V162G and I166L
Familial AF
Unknown
Li et al., 2013 [28 ]
RYR2
S4153R
AF þ CPVT
Gain of function
Zhabyeyev et al., 2013 [29 ]; Kazemian et al., 2011 [30]
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p.Asn57_Gly91
AF þ CPVT
Defects in calcium ion handling
Bhuiyan et al., 2007 [31]
ABBC9
T1547I
Marshall adrenergic AF
Retention of adenosinetriphosphate-induced inhibition of Kþ current
Olson et al., 2007 [24]
NKX2.5
F145S
NPPA
Early-onset lone PAF
Unknown
Ritchie et al., 2012 [7]
AF
Loss of function
Huang et al., 2013 [32]
A117V/S64R
Familial AF
Unknown
Ritchie et al., 2012 [7]
S64R
Familial AF
Accelerated activation and further increase of IKs
Abraham et al., 2010 [33]
c.456–457delAA
Familial AF
Shortened action potential duration and effective refractory
Hodgson-Zingman et al., 2008 [34]
TBX5
G125R
Atypical HOS and AF
Enhanced DNA binding and activation of both the NPPA and Cx40 promoter
Postma et al., 2008 [36]
NUP155
R391H
AF
Inhibition of the export of Hsp70 messenger RNA and nuclear import of Hsp70 protein
Zhang et al., 2008 [35]
GJA1
c.932delC
Lone AF
Dominant-negative effect on gap junctions
Thibodeau et al., 2010 [37]
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Genetic basis of atrial fibrillation Hong and Xiong Table 1 (Continued) Gene
Genotype
Phenotype
Functional effect
References
GJA5
P88S/M163V/G38D/A96S
Idiopathic AF
Dominant-negative effect on gap junctions
Gollob et al., 2006 [38]
I75F
Lone AF
A significant reduction in gap junction coupling conductance
Sun et al., 2013 [39]
K107R/L223M/Q236H/ I257L
Lone AF
Unknown
Shi et al., 2013 [40]
JPH2
E169K
PAF þ HCM
Impaired RyR2 stabilization
Beavers et al., 2013 [41
PITX2c
S37W/Y280X
Familial AF
Unknown
Yang et al., 2013 [42]
T97A
Lone AF
Loss of function
Zhou et al., 2013 [43]
GATA4
S70T, S160T
Familial AF
Significantly decreased transcriptional activity
Yang et al., 2011 [44]
GATA5
G184V, K218T, A266P
Familial AF with VSD/ASD or not
Unknown
Yang et al., 2012 [45]
GATA6
Y235S
Familial AF with VSD/ASD or not
Significantly decreased transcriptional activity
Yang et al., 2012 [46]
Q206P; Y265X
Familial AF with VSD/ASD or not
Unknown
Yang et al., 2012 [46]
&&
]
AF, atrial fibrillation; ASD, atrial septal defect; CPVT, catecholaminergic polymorphic ventricular tachycardia; HCM, hypertrophic cardiomyopathy; HOS, Holt– Oram syndrome; LQT, long QT syndrome; PAF, paroxysmal atrial fibrillation; SQTS, short QT syndrome; VSD, ventricular septal defect.
factor (NPPA) and fibroblast growth factor 10 (FGF10) by binding to T-box-binding elements, often in combination with the NKX2.5 transcription factor. Postma et al. [36] found a gain-of-function TBX5 gene mutation, p.G125R, in a large atypical Holt–Oram syndrome (HOS) family with mild skeletal deformations and paroxysmal atrial fibrillation. In addition, mutations in NPPA and NKX2.5 genes are also associated with the development of atrial fibrillation [7,48]. Secondly, the potential linkage between atrial fibrillation and some cardiogenesis genes, including GATA4, GATA5 and GATA6, has been investigated by Yang et al. [44–46]. Mutations in these genes have been causally implicated in atrial fibrillation and congenital heart diseases, which may suggest a novel insight into the underlying mechanism in the pathogenesis of atrial fibrillation. Although the identified mutations associated with atrial fibrillation have provided great insights into the pathogenesis of atrial fibrillation, some common single-nucleotide polymorphisms (SNPs) are considered to be of relatively broad interest. Three distinct genetic loci on chromosomes, 4q25, 16q22, and 1q21, have been linked to atrial fibrillation in genome-wide association studies (GWAS). Association studies have reported that some common SNPs in genes encoding cardiac ion channels, calcium-handling protein, connexin 40, the renin– angiotensin system [49,50], and inflammatory or anti-inflammatory pathways may predispose to atrial fibrillation development. Olesen et al. [51] replicated the GWAS associations of SNPs in three loci on chromosomes 4q25, 7p31, and 12p12 in a
population of patients with early-onset lone atrial fibrillation. However, the population was relatively small and, consequently, the power to reliably detect and replicate the associations was quite modest. Larger-scale analysis would be a powerful method to assess the risk of atrial fibrillation in SNP carriers. Therefore, Ellinor et al. [52 ] conducted a large-scale meta-analysis of GWAS results based on an initial sample size of 6707 atrial fibrillation patients and 52 426 controls, and a replicated sample size of 5381 atrial fibrillation patients and 10 030 controls. They identified 10 additional atrial fibrillation susceptibility loci which exceeded the preset threshold for genome-wide significance (P < 5 108) (Table 2). The three loci most significantly associated with atrial fibrillation were chromosomes 4q25 in PITX2, 16q22 in ZFHX3, and 1q21 in KCNN3. These results show that atrial fibrillation has multiple genetic associations and identifies new targets for biological investigation. &
GENETIC FACTORS AND THE RISK OF ATRIAL FIBRILLATION RECURRENCE It is known that the mechanisms of induction and perpetuation of atrial fibrillation are complex, and maintenance of sinus rhythm after pharmacological or interventional treatment remains quite challenging, especially in atrial fibrillation complicated with other cardiac disorders. It has been suggested that the recurrence rate appears to be approximately 40–50% after a single procedure and 10–20% after multiple procedures. The
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Molecular genetics Table 2. Summary of GWAS meta-analysis results with P < 5 108 SNP
Locus
Closest gene
Meta P value
RR (95% CI)
rs6666258
1q21
KCNN3-PMVK
2.0 1014
1.18 (1.13–1.23)
11
rs3903239
1q24
PRRX1
9.1 10
1.14 (1.10–1.18)
rs6817105
4q25
PITX2
1.8 1074
1.64 (1.55–1.73)
rs2040862
5q31
WNT8A
3.2 108
1.15 (1.09–1.21)
rs3807989
7q31
CAV1
9.6 1011
0.88 (0.84–0.91)
9
rs10821415
9q22
C9orf3
7.9 10
1.13 (1.08–1.18)
rs10824026
10q22
SYNPO2L
1.7 108
0.85 (0.81–0.90)
rs1152591
14q23
SYNE2
6.2 1010
1.13 (1.09–1.18)
rs7164883
15q24
HCN4
1.3 108
1.16 (1.10–1.22)
rs2106261
16q22
ZFHX3
16
3.2 10
1.24 (1.17–1.30)
CI, confidence interval; GWAS, genome-wide association studies; RR, relative risk; SNP, single-nucleotide polymorphism.
potential linkage of genetic factors and the risk of atrial fibrillation recurrence need to be elucidated in further research. There have been several studies on the association of SNPs with recurrence of atrial fibrillation after pharmacological treatment [53,54 ], electrical cardioversion [55], or catheter ablation [56]. Husser et al. [56] included a total of 195 consecutive patients with drugrefractory paroxysmal or persistent atrial fibrillation who underwent atrial fibrillation catheter ablation, and were the first to genotype two common variants, rs2200733 and rs10033464 on chromosome 4q25, which were independently associated with an increased risk of recurrence of atrial fibrillation after catheter ablation. Recently, Wutzler et al. [57 ] investigated the variations in the human soluble epoxide hydrolase gene responsible for the recurrence of atrial fibrillation after catheter ablation and described that the rs751141 polymorphism of the EPHX2 gene is associated with a significantly increased risk of atrial fibrillation recurrence after catheter ablation. These results may point to a potential role for these common variants in the stratification of catheter ablation by genotype and may guide differential therapy in the future.
risk factors for atrial fibrillation have been described, including hypertension, heart failure, and valve disease. Apart from this, the genetic basis has been considered as a possible pathophysiological substrate for atrial fibrillation. A family history of atrial fibrillation is associated with a two-fold increased risk of the disease. If a family member is affected by atrial fibrillation before age 60, the relative risk increases to 4.7 [58,59]. On the other hand, limited information links specific genetic variants to distinct clinical outcomes for atrial fibrillation. Meanwhile, there are known ethnic differences in prevalence, which will affect the sensitivity of the genetic testing. According to the expert consensus recommendations [60], genetic testing is not indicated for atrial fibrillation patients, based on limited currently available data. It has been proposed that none of the known disease-associated genes has been shown to account for at least 5% of atrial fibrillation. Whether the early-onset lone atrial fibrillation patients can benefit from genetic testing also needs to be investigated. In addition, despite the number of genes related to atrial fibrillation, there is no prognostic or therapeutic impact derived from an atrial fibrillation genetic test result.
CLINICAL IMPLICATIONS OF GENETIC TESTING FOR ATRIAL FIBRILLATION PATIENTS
CONCLUSION
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Current management strategies for atrial fibrillation have had substantial advances or developments in the past few years. However, there still remain some challenges to be solved in this area. On the one hand, the early identification of atrial fibrillation in patients who are at risk and the risk stratification are not fully understood. It is known that numerous 224
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Analyses of candidate genes have revealed a growing number of atrial fibrillation-related genes. A better understanding of the genetic mechanism underlying atrial fibrillation will hopefully lead to a more accurate risk stratification of atrial fibrillation and the discovery of optimal treatment strategies. Further studies based on larger samples will fully elucidate the implication of genetic testing for atrial fibrillation patients. Volume 29 Number 3 May 2014
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Genetic basis of atrial fibrillation Hong and Xiong
Acknowledgements These studies were supported in part by grants from the Ministry of Chinese Education Innovation Team Development Plan (IRT1141); National Basic Research Program of China (973 Program: 2007CB512002; 2008CB517305), the National Natural Science Foundation of China (81070148, 81160023, 30760076). Conflicts of interest There are no conflicts of interest.
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Prevalence and spectrum of GJA5 mutations associated with lone atrial fibrillation. Mol Med Rep 2013; 7:767–774. 41. Beavers DL, Wang W, Ather S, et al. Mutation E169K in junctophilin-2 causes && atrial fibrillation due to impaired RyR2 stabilization. J Am Coll Cardiol 2013; 62:2010–2019. This study uncovers a novel mechanism of Junctophilin-2 in atrial fibrillation. This observation may have important consequences, representing a potential novel therapeutic target for atrial fibrillation. 42. Yang YQ, Xu YJ, Li RG, et al. Prevalence and spectrum of PITX2c mutations associated with familial atrial fibrillation. Int J Cardiol 2013; 168:2873– 2876. 43. Zhou YM, Zheng PX, Yang YQ, et al. A novel PITX2c loss-of-function mutation underlies lone atrial fibrillation. Int J Mol Med 2013; 32:827–834. 44. Yang YQ, Wang MY, Zhang XL, et al. GATA4 loss-of-function mutations in familial atrial fibrillation. Clin Chim Acta 2011; 412:1825–1830. 45. Yang YQ, Wang J, Wang XH, et al. Mutational spectrum of the GATA5 gene associated with familial atrial fibrillation. Int J Cardiol 2012; 157:305– 307. 46. Yang YQ, Li L, Wang J, et al. GATA6 loss-of-function mutation in atrial fibrillation. Eur J Med Genet 2012; 55:520–526. 47. Lu¨bkemeier I, Machura K, Kurtz L, et al. The connexin 40 A96S mutation causes renin-dependent hypertension. J Am Soc Nephrol 2011; 22:1031– 1040.
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Molecular genetics 48. Yang YQ, Gharibeh L, Li RG, et al. GATA4 loss-of-function mutations underlie familial tetralogy of fallot. Hum Mutat 2013; 34:1662–1671. 49. Xiao P, Ling Z, Woo K, et al. Renin-angiotensin system-related gene polymorphisms are associated with risk of atrial fibrillation. Am Heart J 2010; 160:496–505. 50. Wang QS, Li YG, Chen XD, et al. Angiotensinogen polymorphisms and acquired atrial fibrillation in Chinese. J Electrocardiol 2010; 43:373–377. 51. Olesen MS, Holst AG, Jabbari J, et al. Genetic loci on chromosomes 4q25, 7p31, and 12p12 are associated with onset of lone atrial fibrillation before the age of 40 years. Can J Cardiol 2012; 28:191–195. 52. Ellinor PT, Lunetta KL, Albert CM, et al. Meta-analysis identifies six new & susceptibility loci for atrial fibrillation. Nat Genet 2012; 44:670–675. This study is a large-scale meta-analysis of GWAS results to identify additional atrial fibrillation susceptibility loci. 53. Darbar D, Motsinger AA, Ritchie MD, et al. Polymorphism modulates symptomatic response to antiarrhythmic drug therapy in patients with lone atrial fibrillation. Heart Rhythm 2007; 4:743–749. 54. 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. This study suggests the association of SNPs with response to antiarrhythmic drugs in atrial fibrillation patients.
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Volume 29 Number 3 May 2014
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Genetic basis of atrial fibrillation Kui Hong a,b and Qinmei Xiong a
Purpose of review Atrial fibrillation, the most common cardiac supraventricular arrhythmia, affects more than 5 million people worldwide. Increasing evidence has demonstrated that genetic factors play an important role in the pathogenesis of atrial fibrillation, and multiple genes responsible for atrial fibrillation have been identified. This review will focus on the recent findings in atrial fibrillation genetic studies and discuss the clinical implications of exploring the atrial fibrillation genetic basis. Recent findings The advent of the candidate gene approach and genome-wide association studies has facilitated the process of investigating the complex genetic background underlying the pathogenesis of atrial fibrillation. Recent genetic investigations have offered further insights into the predisposing genes encoding ion channels, connexin, atrial natriuretic peptide, RyR2, T-box transcription factor, nucleoporins and zinc-finger transcription factor. Common single-nucleotide polymorphisms are important factors in the development of lone atrial fibrillation, recurrent atrial fibrillation or atrial fibrillation complicated with cardiac disorders. Summary Analyses of candidate genes have revealed a growing number of atrial fibrillation-related genes. A better understanding of the genetic mechanism underlying atrial fibrillation would be expected to lead to more accurate risk stratification of atrial fibrillation and the discovery of optimal clinical treatment strategies that carry maximal efficacy and minimal risk in a manner that is consistent with the vision of pharmacogenomics. Keywords atrial fibrillation, gene, genetic testing
INTRODUCTION The prevalence of atrial fibrillation increases markedly with age, ranging from approximately 1% in the general population to approximately 10% in those aged over 75 years [1]. With the accelerating aging population process and the improved survival of patients with other cardiovascular disorders, atrial fibrillation is estimated to increase five-fold in prevalence by 2050 [2]. The presence of atrial fibrillation can cause serious complications and can independently increase the risk of mortality and morbidity. Atrial fibrillation confers a five-fold increase in the risk of stroke and approximately doubles mortality, resulting in a major financial burden to patients and healthcare systems. While the underlying mechanisms of atrial fibrillation are complex and not well understood, multiple potential pathways and risk factors have been investigated. Atrial fibrillation is generally known as a common complication in various cardiac and systemic disorders. Valvular heart disease, www.co-cardiology.com
hypertension, ischemic heart disease and hyperthyroidism are the most common causal risk factors. In some cases, atrial fibrillation can also exist in the absence of the previously mentioned predisposing factors and is defined as lone atrial fibrillation, of which up to 15% exhibits familial clustering. Since the first chromosomal locus was identified in 1997, a genetic susceptibility to the development of atrial fibrillation and emerging evidence has strongly implicated hereditary determinants for atrial fibrillation [3]. In this review article, we will focus on the recent findings in atrial fibrillation genetic studies a Cardiovascular Department and bThe Key Laboratory of Molecular Medicine, the Second Affiliated Hospital of Nanchang University, Nanchang, China
Correspondence to Kui Hong, MD, PhD, Cardiovascular Department, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Nanchang 330006, China. Tel: +86 791 86312917; e-mail: [email protected]. Curr Opin Cardiol 2014, 29:220–226 DOI:10.1097/HCO.0000000000000051 Volume 29 Number 3 May 2014
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Genetic basis of atrial fibrillation Hong and Xiong
KEY POINTS Since the first mutation gene KCNQ1 responsible for atrial fibrillation was identified in 2003, genetic studies have identified mutations associated with atrial fibrillation in at least 24 genes. Some SNPs are responsible for the risk of atrial fibrillation recurrence after pharmacological treatment, electrical cardioversion or catheter ablation. Routine genetic testing is not indicated for sporadic atrial fibrillation patients, based on limited currently available data.
and discuss the clinical implications of exploring the genetic basis of atrial fibrillation in this field.
some exceptional cases. The SCN5A mutation p.M1875T associated with familial atrial fibrillation displayed a gain-of-function type modulation of cardiac Naþ channels, which is a novel mechanism predisposing to increased atrial excitability and familial atrial fibrillation [9]. Mutations in KCNA5, encoding the ultra-rapid delayed rectifier potassium current (IKur), can result in a loss-of-function effect on IKur current and eventually lead to atrial fibrillation [21–23]. Mutations in the RYR2 gene contribute to abnormal Ca2þ handling in cardiomyocytes, which may produce various arrhythmias, including catecholaminergic polymorphic ventricular tachycardia (CPVT). Recent genetic findings have shown that p.S4153R mutation in RYR2 gene is a gain-of-function mutation associated with a clinical phenotype characterized by both CPVT and atrial fibrillation [29 ,30]. JPH2 is believed to play an important role in sarcoplasmic reticulum Ca2þ handling and modulation of RYR2. Beavers et al. [41 ] screened 203 unrelated hypertrophic cardiomyopathy patients and uncovered a novel JPH2 missense mutation, p.E169K, in two patients with juvenileonset paroxysmal atrial fibrillation. Further analysis suggested that JPH2-mediated destabilization of RYR2 due to a loss-of-function mutation can promote a sarcoplasmic reticulum Ca2þ leak and lead to CPVT and atrial fibrillation. These data may underscore the importance of Ca2þ dysregulation as a fundamental mechanism for both atrial and ventricular tachyarrhythmias, representing a potential novel therapeutic target for atrial fibrillation. Gap junctional proteins significantly mediate the electrical coupling of cardiomyocytes, which enables effective propagation of electrical activation and contraction of cardiomyocytes. Connexins are key members of gap junctional proteins, including connexin43 (Cx43) and connexin40 (Cx40), which are highly expressed in atrial tissues. Genetic studies have suggested that mutations in GJA1 and GJA5, the genes encoding Cx43 and Cx40, respectively, are also involved in the pathogenesis of atrial fibrilla¨ bkemeier et al. [47] generated tion [37–40]. Lu transgenic Cx40A96S mice as a model for atrial fibrillation and proposed the possibility of investigating the key effect of the GJA5 mutation in the etiopathology of certain cases of genetically mediated human atrial fibrillation. Recent findings may warrant a new investigation into several genes linked to the overlapping phenotype of congenital heart/skeletal defects and atrial fibrillation. Firstly, TBX5 is expressed in the embryonic heart and regulates transcription of downstream genes such as the atrial natriuretic &
GENE VARIANTS UNDERLYING ATRIAL FIBRILLATION In 1997, based on linkage analysis, 10q22-q24 as the genetic locus was identified in three families with autosomal dominant atrial fibrillation [3]. Although the exact genes responsible for atrial fibrillation in this region remain unknown, the scientific results instigated exploring the genetic characteristics of atrial fibrillation. Over the past decade, since the first mutation gene KCNQ1 responsible for atrial fibrillation was identified [4], genetic studies have identified mutations associated with atrial fibrillation in at least 25 genes: KCNQ1 [4–8], SCN5A [7,9–12], KCNH2 [13], KCNE2 [14], KCNE3 [15,16], KCNE5 [17], KCNJ2 [18–20], KCNA5 [7,21–23], ABCC9 [24], SCN1B [25], SCN2B [25], SCN3B [26,27], SCN4B [28 ], ryanodine receptor 2 (RYR2) [29 ,30,31], NKX2.5 [7,32], NPPA [7,33,34], T-box transcription factor 5 (TBX5) [35], NUP155 [36], GJA1 [37], GJA5 [38–40], Junctophilin 2 (JPH2) [41 ], PITX2c [42,43], GATA4 [44], GATA5 [45], and GATA6 [46] (Table 1). Mutations have also been identified in the patient population with atrial fibrillation complicated with other disorders. As exemplified by the findings of Hong et al. [5], a de-novo missense p.V141M mutation in KCNQ1 was identified in a baby girl who was diagnosed with atrial fibrillation with slow ventricular response and a short QT interval. Recent data have shown that almost all of the potassium channel and sodium channel genes are associated with the development of atrial fibrillation. Further functional analyses of the ion channel gene mutation have revealed that gain-of-function effects on potassium current and loss-of-function effects on sodium current can generally be responsible for the pathogenesis of atrial fibrillation, with &
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Molecular genetics Table 1. Gene mutations responsible for AF Gene KCNQ1
Genotype
Phenotype
Functional effect
References
Gain-of-function effect on Iks current
S140G
Familial AF
V141M
SQTS þ AF
Q147R
AF þ prolonged QT interval
Kv7.1 gain of function in the atria
Lundby et al., 2007 [6]
IAP54-56
Familial AF
Unknown
Ritchie et al., 2012 [7]
Chen et al., 2003 [4] Hong et al., 2005 [5]
R231C
AF þ LQT1
Gain-of-function effect on Iks current
Bartos et al., 2011 [8]
KCNH2
N588K
AF þ SQTS
Gain-of-function effect on Ikr current
Brugada et al., 2004 [13]
KCNE2
R27C
Familial AF
Gain-of-function effect on Ikr current
Yang et al., 2004 [14]
KCNE3
R53H
Familial AF
Unknown
Zhang et al., 2005 [15]
V17M
Early-onset lone AF
Gain-of-function effect on Ikr current
Lundby et al., 2008 [16]
L65F
AF þ ischemic heart disease þ mild hypertension
Gain-of-function effect on Iks current
Ravn et al., 2008 [17]
Gain-of-function effect on Ikr current
KCNE5 KCNJ2
KCNA5
G277A
AF
G514A
SQTS þ AF
E299V
PAF þ SQTS
T527M/A576V/E610K
Familial AF
E375X
Lone AF at age 35
71–81 del
Lone AF at age of 34
Xia et al., 2005 [18] Priori et al., 2005 [19] Deo et al., 2013 [20] Yang et al., 2009 [21]
Loss-of-function effect on Ikur currents
Olson et al., 2006 [22] Yang et al., 2010 [23] Ritchie et al., 2012 [7]
SCN5A
M1875T
Familial AF
Gain-of-function effect on INa current
Makiyama et al., 2008 [9]
D1275N
AF þ DCM
Loss-of-function effect on INa current
Olson et al., 2005 [10]
N1986K
Familial AF
Loss-of-function effect on INa current
Ellinor et al., 2008 [11]
T220I/R1897W/T1304M/ F1596I/R1626H/ D1819N/R340Q/V1951M
A cohort of patients with early-onset lone AF
Compromised transient peak current and increased sustained current
Olesen et al., 2012 [12]
A572D/E428K/H445D/ N470K/V1951M/L461V
Familial AF
Unknown
Ritchie et al., 2012 [7]
SCN1B
R85H/D153N
PAF and moderate aortic stenosis/lone PAF
Loss-of-function effect on INa current
Watanabe et al., 2009 [25]
SCN2B
R28Q/R28W
PAF and hypertension/PAF and hypertension
Loss-of-function effect on INa current
Watanabe et al., 2009 [25]
SCN3B
R6K/L10P/M161T
Early-onset lone AF
Loss of function in the sodium current
Olesen et al., 2011 [26]
A130V
Lone AF
Functional dominant-negative mutation
Wang et al., 2010 [27]
SCN4B
V162G and I166L
Familial AF
Unknown
Li et al., 2013 [28 ]
RYR2
S4153R
AF þ CPVT
Gain of function
Zhabyeyev et al., 2013 [29 ]; Kazemian et al., 2011 [30]
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p.Asn57_Gly91
AF þ CPVT
Defects in calcium ion handling
Bhuiyan et al., 2007 [31]
ABBC9
T1547I
Marshall adrenergic AF
Retention of adenosinetriphosphate-induced inhibition of Kþ current
Olson et al., 2007 [24]
NKX2.5
F145S
NPPA
Early-onset lone PAF
Unknown
Ritchie et al., 2012 [7]
AF
Loss of function
Huang et al., 2013 [32]
A117V/S64R
Familial AF
Unknown
Ritchie et al., 2012 [7]
S64R
Familial AF
Accelerated activation and further increase of IKs
Abraham et al., 2010 [33]
c.456–457delAA
Familial AF
Shortened action potential duration and effective refractory
Hodgson-Zingman et al., 2008 [34]
TBX5
G125R
Atypical HOS and AF
Enhanced DNA binding and activation of both the NPPA and Cx40 promoter
Postma et al., 2008 [36]
NUP155
R391H
AF
Inhibition of the export of Hsp70 messenger RNA and nuclear import of Hsp70 protein
Zhang et al., 2008 [35]
GJA1
c.932delC
Lone AF
Dominant-negative effect on gap junctions
Thibodeau et al., 2010 [37]
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Genetic basis of atrial fibrillation Hong and Xiong Table 1 (Continued) Gene
Genotype
Phenotype
Functional effect
References
GJA5
P88S/M163V/G38D/A96S
Idiopathic AF
Dominant-negative effect on gap junctions
Gollob et al., 2006 [38]
I75F
Lone AF
A significant reduction in gap junction coupling conductance
Sun et al., 2013 [39]
K107R/L223M/Q236H/ I257L
Lone AF
Unknown
Shi et al., 2013 [40]
JPH2
E169K
PAF þ HCM
Impaired RyR2 stabilization
Beavers et al., 2013 [41
PITX2c
S37W/Y280X
Familial AF
Unknown
Yang et al., 2013 [42]
T97A
Lone AF
Loss of function
Zhou et al., 2013 [43]
GATA4
S70T, S160T
Familial AF
Significantly decreased transcriptional activity
Yang et al., 2011 [44]
GATA5
G184V, K218T, A266P
Familial AF with VSD/ASD or not
Unknown
Yang et al., 2012 [45]
GATA6
Y235S
Familial AF with VSD/ASD or not
Significantly decreased transcriptional activity
Yang et al., 2012 [46]
Q206P; Y265X
Familial AF with VSD/ASD or not
Unknown
Yang et al., 2012 [46]
&&
]
AF, atrial fibrillation; ASD, atrial septal defect; CPVT, catecholaminergic polymorphic ventricular tachycardia; HCM, hypertrophic cardiomyopathy; HOS, Holt– Oram syndrome; LQT, long QT syndrome; PAF, paroxysmal atrial fibrillation; SQTS, short QT syndrome; VSD, ventricular septal defect.
factor (NPPA) and fibroblast growth factor 10 (FGF10) by binding to T-box-binding elements, often in combination with the NKX2.5 transcription factor. Postma et al. [36] found a gain-of-function TBX5 gene mutation, p.G125R, in a large atypical Holt–Oram syndrome (HOS) family with mild skeletal deformations and paroxysmal atrial fibrillation. In addition, mutations in NPPA and NKX2.5 genes are also associated with the development of atrial fibrillation [7,48]. Secondly, the potential linkage between atrial fibrillation and some cardiogenesis genes, including GATA4, GATA5 and GATA6, has been investigated by Yang et al. [44–46]. Mutations in these genes have been causally implicated in atrial fibrillation and congenital heart diseases, which may suggest a novel insight into the underlying mechanism in the pathogenesis of atrial fibrillation. Although the identified mutations associated with atrial fibrillation have provided great insights into the pathogenesis of atrial fibrillation, some common single-nucleotide polymorphisms (SNPs) are considered to be of relatively broad interest. Three distinct genetic loci on chromosomes, 4q25, 16q22, and 1q21, have been linked to atrial fibrillation in genome-wide association studies (GWAS). Association studies have reported that some common SNPs in genes encoding cardiac ion channels, calcium-handling protein, connexin 40, the renin– angiotensin system [49,50], and inflammatory or anti-inflammatory pathways may predispose to atrial fibrillation development. Olesen et al. [51] replicated the GWAS associations of SNPs in three loci on chromosomes 4q25, 7p31, and 12p12 in a
population of patients with early-onset lone atrial fibrillation. However, the population was relatively small and, consequently, the power to reliably detect and replicate the associations was quite modest. Larger-scale analysis would be a powerful method to assess the risk of atrial fibrillation in SNP carriers. Therefore, Ellinor et al. [52 ] conducted a large-scale meta-analysis of GWAS results based on an initial sample size of 6707 atrial fibrillation patients and 52 426 controls, and a replicated sample size of 5381 atrial fibrillation patients and 10 030 controls. They identified 10 additional atrial fibrillation susceptibility loci which exceeded the preset threshold for genome-wide significance (P < 5 108) (Table 2). The three loci most significantly associated with atrial fibrillation were chromosomes 4q25 in PITX2, 16q22 in ZFHX3, and 1q21 in KCNN3. These results show that atrial fibrillation has multiple genetic associations and identifies new targets for biological investigation. &
GENETIC FACTORS AND THE RISK OF ATRIAL FIBRILLATION RECURRENCE It is known that the mechanisms of induction and perpetuation of atrial fibrillation are complex, and maintenance of sinus rhythm after pharmacological or interventional treatment remains quite challenging, especially in atrial fibrillation complicated with other cardiac disorders. It has been suggested that the recurrence rate appears to be approximately 40–50% after a single procedure and 10–20% after multiple procedures. The
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Molecular genetics Table 2. Summary of GWAS meta-analysis results with P < 5 108 SNP
Locus
Closest gene
Meta P value
RR (95% CI)
rs6666258
1q21
KCNN3-PMVK
2.0 1014
1.18 (1.13–1.23)
11
rs3903239
1q24
PRRX1
9.1 10
1.14 (1.10–1.18)
rs6817105
4q25
PITX2
1.8 1074
1.64 (1.55–1.73)
rs2040862
5q31
WNT8A
3.2 108
1.15 (1.09–1.21)
rs3807989
7q31
CAV1
9.6 1011
0.88 (0.84–0.91)
9
rs10821415
9q22
C9orf3
7.9 10
1.13 (1.08–1.18)
rs10824026
10q22
SYNPO2L
1.7 108
0.85 (0.81–0.90)
rs1152591
14q23
SYNE2
6.2 1010
1.13 (1.09–1.18)
rs7164883
15q24
HCN4
1.3 108
1.16 (1.10–1.22)
rs2106261
16q22
ZFHX3
16
3.2 10
1.24 (1.17–1.30)
CI, confidence interval; GWAS, genome-wide association studies; RR, relative risk; SNP, single-nucleotide polymorphism.
potential linkage of genetic factors and the risk of atrial fibrillation recurrence need to be elucidated in further research. There have been several studies on the association of SNPs with recurrence of atrial fibrillation after pharmacological treatment [53,54 ], electrical cardioversion [55], or catheter ablation [56]. Husser et al. [56] included a total of 195 consecutive patients with drugrefractory paroxysmal or persistent atrial fibrillation who underwent atrial fibrillation catheter ablation, and were the first to genotype two common variants, rs2200733 and rs10033464 on chromosome 4q25, which were independently associated with an increased risk of recurrence of atrial fibrillation after catheter ablation. Recently, Wutzler et al. [57 ] investigated the variations in the human soluble epoxide hydrolase gene responsible for the recurrence of atrial fibrillation after catheter ablation and described that the rs751141 polymorphism of the EPHX2 gene is associated with a significantly increased risk of atrial fibrillation recurrence after catheter ablation. These results may point to a potential role for these common variants in the stratification of catheter ablation by genotype and may guide differential therapy in the future.
risk factors for atrial fibrillation have been described, including hypertension, heart failure, and valve disease. Apart from this, the genetic basis has been considered as a possible pathophysiological substrate for atrial fibrillation. A family history of atrial fibrillation is associated with a two-fold increased risk of the disease. If a family member is affected by atrial fibrillation before age 60, the relative risk increases to 4.7 [58,59]. On the other hand, limited information links specific genetic variants to distinct clinical outcomes for atrial fibrillation. Meanwhile, there are known ethnic differences in prevalence, which will affect the sensitivity of the genetic testing. According to the expert consensus recommendations [60], genetic testing is not indicated for atrial fibrillation patients, based on limited currently available data. It has been proposed that none of the known disease-associated genes has been shown to account for at least 5% of atrial fibrillation. Whether the early-onset lone atrial fibrillation patients can benefit from genetic testing also needs to be investigated. In addition, despite the number of genes related to atrial fibrillation, there is no prognostic or therapeutic impact derived from an atrial fibrillation genetic test result.
CLINICAL IMPLICATIONS OF GENETIC TESTING FOR ATRIAL FIBRILLATION PATIENTS
CONCLUSION
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Current management strategies for atrial fibrillation have had substantial advances or developments in the past few years. However, there still remain some challenges to be solved in this area. On the one hand, the early identification of atrial fibrillation in patients who are at risk and the risk stratification are not fully understood. It is known that numerous 224
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Analyses of candidate genes have revealed a growing number of atrial fibrillation-related genes. A better understanding of the genetic mechanism underlying atrial fibrillation will hopefully lead to a more accurate risk stratification of atrial fibrillation and the discovery of optimal treatment strategies. Further studies based on larger samples will fully elucidate the implication of genetic testing for atrial fibrillation patients. Volume 29 Number 3 May 2014
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Genetic basis of atrial fibrillation Hong and Xiong
Acknowledgements These studies were supported in part by grants from the Ministry of Chinese Education Innovation Team Development Plan (IRT1141); National Basic Research Program of China (973 Program: 2007CB512002; 2008CB517305), the National Natural Science Foundation of China (81070148, 81160023, 30760076). Conflicts of interest There are no conflicts of interest.
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Volume 29 Number 3 May 2014
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