- Open Access
Molecular genetics of atrial fibrillation
Genome Medicine volume 1, Article number: 54 (2009)
Atrial fibrillation (AF) is the most common persistent cardiac dysrhythmia and the number one cause of arrhythmia-related hospitalizations. In addition, AF is a major contributor to stroke. With life expectancies increasing, the growing global disability from AF has crippling implications for society. Several family studies have shown a strong polygenetic predisposition for AF but, so far, most of the linkage analysis and candidate gene studies have discovered only monogenic, rare, deleterious mutations. Recent breakthroughs in high-throughput genotyping technology have allowed improved scanning of the genome with greater statistical power to detect susceptibility alleles for AF. Using this technology, a region on 4q25 has now been identified and validated in thousands of cases as a common susceptibility factor for AF with an odds ratio of over 3.0 for homozygotes. The Paired-like homeodomain transcription factor 2 (PITX2) gene, which is involved in embryonic cardiac development, has now been identified as the causal variant for the 4q25 susceptibility locus. Additional susceptibility variants are anticipated that will have direct ramifications for prognosis and treatment of this highly pervasive and clinically significant disorder.
Atrial fibrillation (AF) has an enormous societal impact because of its very high incidence, its potential for devastating clinical consequences, the difficulty of its management and its associated financial burdens [1–4]. It is the most common persistent cardiac dysrhythmia and also the most common cause of arrhythmia-related hospitalizations [5, 6]. The relative risk of death for people with AF is over 20% higher per year than that of age-matched controls, with stroke accounting for the majority of that greater risk . Currently, it is estimated that AF affects approximately 2.3 million people in the United States, with an expected fivefold increase in prevalence by 2050 . With life expectancies increasing in both developed and developing countries, the growing global disability and financial burden of AF has crippling implications for society.
Given these projections, new strategies are desperately needed to prevent and better treat AF. Over the past 2 years, there has been an unprecedented series of genomic findings giving us considerable insight into the underpinnings of the most common diseases, including diabetes mellitus, myocardial infarction, various types of cancer and AF . Here, we review the recent advances in the genetics of AF and suggest routes towards an individualized medical approach.
Scanning the genome for susceptibility loci
Hypertension, heart failure, advanced age and diabetes are well known risk factors for AF [9, 10]. However, significant proportions of patients, up to 30% in some large studies, develop AF in the absence of these factors ('lone' AF) [11, 12]. Furthermore, multivariable modeling has shown that AF, particularly if premature in onset, more than triples the risk of future disease in offspring . Evidence for even stronger heritability is seen in those with a first-degree relative diagnosed with lone AF before the age of 60; these patients were five times more likely to develop AF than the general population [14, 15].
Despite the abundance of data implicating a genetic basis of AF, we have been unsuccessful in fully delineating its pathobiology. Several studies have identified rare, deleterious 'private' mutations resulting in familial AF [16–21]. However, these variants provide little, if any, explanation for the common AF phenotype [22, 23]. Like diabetes and obesity, AF is a complex trait involving multiple genetic and environmental factors [24, 25].
Earlier methods used in scanning the genome for susceptibility markers for AF relied chiefly on linkage studies using microsatellite markers (short tandem repeat sequences) . This approach required the laborious accrual of hundreds of family members with affected and unaffected siblings. Subsequently, using 400 microsatellite markers distributed evenly across the genome every 10 centimorgans (or approximately every 10 million base pairs), the genomes were systematically assessed to search for a 'linkage peak' or extensive allele sharing. Such a linkage peak would indicate that a causal gene was near or perhaps in linkage disequilibrium (LD; inherited as a block without recombination) with the microsatellite marker. However, identifying a causal locus interspersed over a million base pairs has proven to be difficult, as evidenced by the limited replication of genomic associations discovered through this process .
In the past 2 years, however, there have been dramatic advances in high-throughput genotyping, allowing much greater statistical power when searching for susceptibility loci . First, large-scale efforts have led to the identification of the approximately 11 million base pairs that commonly vary among individuals. These single nucleotide polymorphisms (SNPs) represent approximately 0.3% of the total genome but account for the majority of human genetic variation. Second, we have found that these base pairs are not inherited independently, but as 'units' or 'bins' that are in LD with disease-causing alleles. This advance has served as our 'global positioning system' by enhancing our ability to home in on areas of the genome of pathobiological relevance.
Moreover, we now know that the genotype of one SNP may be sufficient to infer the genotype of all other SNPs within a given haplotype block, thereby 'tagging' an entire region of interest (Figure 1). The International HapMap project demonstrated that 300,000-500,000 tag SNPs in European or Asian populations or 1.1 million tag SNPs in African individuals of Yoruban descent is sufficient to capture the majority of our common genetic variation (common variants are taken here as those with a greater than 5% minor allele frequency) [28, 29]. Thus, less than 0.03% of all nucleotides comprising the human genome are enough to provide a window to index our biological individuality.
Another distinct advantage provided by using tag SNPs in high-throughput genotyping includes the ability to recruit sporadic cases of AF in a cohort instead of sibling-pairs or 'multiplex' families . Rapid accumulation of tens of thousands of sporadic cases for establishing associations of alleles with complex traits has dramatically increased the specificity, accuracy and reproducibility of findings. So far, genetic susceptibility for over 40 common diseases has been identified and validated in the last two years using these techniques .
Candidate gene and linkage analysis
In 1997, Brugada and colleagues  reported the first chromosomal susceptibility locus (10q22-q24) for familial autosomal dominant AF in three families using linkage analysis. Subsequently, using a candidate gene approach, one possible gene was identified: DLG5 (discs large homolog 5) . Efforts thus far have not validated this susceptibility locus. Ellinor et al.  had similar difficulty in identifying a causative gene in 34 members of a family with autosomal dominant AF mapping to susceptibility locus 6q14-16 .
Multiple mutations involving potassium-channel genes have been associated with familial AF [18, 19, 32]. Chen and colleagues , while studying a four-generation Chinese family, identified a mutation in the first transmembrane-spanning domain of the potassium channel gene KCNQ1. This gain-of-function mutation resulted in increased K+ current density . Mutations in other regions of this gene have also been documented in the long QT syndrome type 1 (LQT1) . Subsequently, several other potassium rectifier current gene mutations were identified, including KCNE2, KCNJ2 and KCNH2 (Table 1) [18, 19, 32, 35]. These genes all have gain-of-function phenotypes that result in shortening of the action potential duration (APD); this shortening predisposes atrial tissue to reentrant arrhythmias - a hypothesized major cause of AF generation and propagation [36, 37]. Certainly, positive effects from class III anti-arrhythmics, such as amiodarone and the recently approved dronaderone, which lengthen APD and maintain sinus rhythm, support this hypothesis .
Recently, Chen et al.  studied 157 unrelated patients with lone AF and 314 matched controls using a candidate gene approach. A common loss-of-function H558R mutation was identified in the SCN5A gene conferring an odds ratio (OR) of 1.6. The at-risk allele was present in 30% of cases but in only 21% of controls (P = 0.002). The decreased sodium current associated with this mutation affects phase 0 of the cardiac action potential, creating a shorter wavelength of conduction velocity and potentially more stable AF.
One of the most elegant studies of AF  ever conducted used functional genomics to study a rare autosomal recessive mutation on 5p13 linked to neonatal AF and sudden death . Using fine mapping, the authors  identified a homozygous mutation, R391H, in the nucleoporin 155 gene (NUP155). Nucleoporins are part of the nuclear pore complex (NPC),which is an evolutionary conserved structure serving as a highway for transport of mRNA’s and proteins between the nucleus and cytoplasm . Homozygous knockout mice (nup155-/-) died during embryogenesis, whereas heterozygous mice had AF and showed expression levels of mouse nup155 mRNA and protein that were less than half the wild-type levels (a statistically significant reduction). Furthermore, nup155+/- mice showed significantly reduced export of heat shock protein 70 (hsp70) - a protein vital to cellular viability - confirming a dysfunctional NPC. This is the first study to link the NPC to cardiovascular disease. Investigation of the NPC as an etiology for other arrhythmogenic disorders might be worthwhile.
Connexin 40 is a gap junction protein expressed selectively in atrial myocytes that mediates coordinated electrical activity in the atria [42–44]. Because defects in this protein impair electrical coupling between atrial cells, it is speculated that the resulting conduction heterogeneity might enable AF . In an elegantly conducted study, Gollob et al.  identified novel mutations in the connexin 40 gene (GJA5) in resected atrial tissue from patients with lone AF. Interestingly, none of the same mutations isolated from the cardiac tissue were identified in the peripheral blood lymphocytes, indicating the de novo nature of the mutation. This was the first study in AF genetics to use site-specific tissue to identify novel somatic variants. The role of somatic mutations in connexin 40 needs to be further validated, as 11 of the 15 patients did not show the mutation at the tissue level.
Two hormonal genes critically interlaced with various facets of the cardiovascular system were recently implicated in AF [45–47]. Hodgson-Zingman et al.  mapped a susceptibility locus in a family with 11 clinically affected members to 1p36-p35. This heterozygous variant resulted in a frameshift mutation in the gene encoding natriuretic peptide precursor A (NPPA), which also encodes atrial natriuretic peptide (ANP). Through stimulation of cyclic GMP, ANP has a vital role in the regulation of intravascular blood volume and vascular tone through natriuresis, diuresis and vasodilation . ANP also modulates currents of sodium, calcium and potassium channels in cardiac myocytes . The frameshift mutation abolishes the stop codon and extends the reading frame. The resulting protein shortens atrial monophasic action potentials in an isolated whole-heart animal model, which provides a plausible hypothesis for its role in AF .
An association between genetic polymorphisms in genes of the renin-angiotensin system and nonfamilial AF has also been reported . Using a candidate gene approach, Tsai and colleagues  demonstrated an increased risk of AF in 250 patients with nonvalvular AF. Three polymorphisms in the angiotensin converting enzyme, angiotensinogen and angiotensin II type I receptor genes were implicated, with ORs for all three being between 2.0 and 3.3. The effects were not additive. The renin-angiotensin system has previously been shown to induce atrial fibrosis, which increases conduction heterogeneity and facilitates reentrant arrhythmias [45, 49].
Genes believed to mediate inflammation are now also being found to segregate with AF . In one small series, SNPs in the endothelial nitric oxide synthase gene and the minK 38G variant were shown to be synergistic in their risk for AF (OR 2.11) . A single polymorphism in the matrix metalloproteinase-2 (MMP2) gene and an A592 polymorphism of the interleukin-10 gene were also significantly associated with AF in another small series . The potential pathobiology of inflammation-induced AF is currently being explored.
Genome-wide association studies
Recently, using high-throughput SNP genotyping, Gudbjartsson and colleagues  performed a genome-wide association study (GWAS) of over 300,000 SNPs in over 4,000 AF cases and 20,000 controls across four independent European and Han Chinese populations. Three SNPs in the same LD block on chromosome 4q25 strongly correlated with AF (P = 2.1 × 10-9, 1.6 × 10-10 and 1.9 × 10-9). Approximately 35% of Europeans and 52% of Chinese people are known to carry at least one of these variants, but no individual was noted to have all three variants, indicating an embryonic lethal combination. Strikingly, the ORs for European and Chinese individuals homozygous for one variant, the rs2200733T allele, were 3.64 and 1.7, respectively. So far, these are some of the highest ORs documented for complex trait susceptibility using genome-wide SNP association technology. Kääb and colleagues have recently reproduced this AF susceptibility locus in 4 additional cohorts .
Currently, there is no known annotated gene present in the LD block containing the SNPs identified on 4q25. However, recent data strongly implicate the PITX2 (Paired-like homeodomain transcription factor 2) gene in the immediate upstream block as the causative agent . Chung et al.  conducted a GWAS using 200,000 SNPs in 138 AF cases and 546 controls. A single SNP (rs4611994) in the same LD block on 4q25 met genome-wide significance and was again genotyped in 46 left atrial appendage tissue samples, with PITX2 expression levels also obtained. This analysis demonstrated a significant association of the rs4611994 genotype with the C isoform of PITX2.
PITX2 is an interesting candidate gene for AF susceptibility given that it is known to act in cardiac development by directing asymmetric morphogenesis of the heart . Knockout models of pitx2 in mice have been shown to inhibit sinoatrial node formation in the left atrium.  (Figure 2). Recently, PITX2 was also demonstrated to be necessary for the development of the pulmonary myocardium, the sleeve of cardiomyocytes that extends from the left atrium to the initial portion of the pulmonary vein . This area has been implicated as a source for the ectopic atrial activity necessary for the initiation and propagation of AF . Appropriate gene therapy early in life in patients with the PITX2 variant might prevent early-onset AF.
A recent GWAS on ischemic stroke patients yielded striking results . Over 300,000 SNPs were analyzed in approximately 5,000 ischemic stroke cases and over 30,000 controls. Surprisingly, the authors  found that the SNP on 4q25 previously reported to be associated with AF also segregated with ischemic stroke, and specifically the cardioembolic and cryptogenic subtype of ischemic stroke (ORs 1.54 and 1.23). This highlights the role of AF as a root cause of stroke in a significant proportion of patients. The role of AF in stroke was further confirmed recently when data from mobile telemetry units showed brief runs of AF in over 25% of patients diagnosed with cryptogenic stroke . Thus, for the first time, a GWAS has not only identified a region of the genome associated with a disease, ischemic stroke, but has also shed light on another disease, AF, with immediate and direct ramifications for treatment strategies. An appropriate genomically informed approach might be to assess the status of common variants of PITX2 in all patients with cryptogenic stroke followed by telemetry monitoring and anticoagulation in those at risk (Figure 3). A pharmacological approach to the potassium channelopathy could potentially be developed to promote gene-specific, individualized prevention. Such a strategy would serve as a reference standard on how to use human genomics to tailor therapy to each patient's biological makeup.
The chain of discoveries in complex trait genomics uncovered over the past 2 years using genome-wide association technology is unprecedented . Currently, susceptibility markers for over 70 diseases have been identified and additional variants are anticipated for many cancers, and cardiovascular and neurological diseases. Collectively, these studies have the potential to change the practice of medicine radically. However, there are several areas of the genome that still need to be explored and that probably have a significant role in explaining the heritability of many common diseases . Specifically, structural variants including insertion-deletions (indels), block substitutions, inversions and copy number variants have recently been shown to account for at least 20% of all genetic variation in humans. Such variants are only now being investigated. So far, GWASs have focused on only SNP variants with a minor allele frequency of over 5%. However, given the relatively modest odds ratios seen recently with common polymorphisms, it is very likely that rare variants confer a substantial risk or protection from disease. Such was the case with rare type 1 diabetes loci that were recently found to halve the risk for developing the disease . Only large-scale resequencing of the genome will enable the discovery of these low-frequency variants, which would otherwise be missed.
Another challenge will be to show, through well designed prospective studies, that new susceptibility variants offer incremental value in screening and treatment over traditional standards . Such studies will be of utmost importance given that additional common, rare and structural variations predisposing us to common diseases are likely to surface rapidly in the near future. We also must be aware that alleles conferring susceptibility in those of European descent might be protective or not confer any risk in those of other ancestries. Only through comprehensive study of heterogeneous populations will we be able to fully define the genetics of complex trait predisposition .
Finally, appropriate phenotypic expression, metabolomic and proteomic studies will be vital in elucidating the functional genomics of susceptibility variants. The aggregate result of the above efforts will hopefully propel us into an era of medicine in which we no longer use a 'shotgun' approach in treatment of our most common and burdensome diseases, but instead use a particularized approach made specifically for the individual patient based on his or her unique pathobiology.
atrial natriuretic peptide
action potential duration
genome-wide association study
nuclear pore complex
single nucleotide polymorphism.
Wattigney WA, Mensah GA, Croft JB: Increasing trends in hospitalization for atrial fibrillation in the United States, 1985 through 1999: implications for primary prevention. Circulation. 2003, 108: 711-716.
Wolf PA, Mitchell JB, Baker CS, Kannel WB, D'Agostino RB: Impact of atrial fibrillation on mortality, stroke, and medical costs. Arch Intern Med. 1998, 158: 229-234.
Benjamin EJ, Wolf PA, D'Agostino RB, Silbershatz H, Kannel WB, Levy D: Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation. 1998, 98: 946-952.
Wolf PA, Abbott RD, Kannel WB: Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991, 22: 983-988.
Feinberg WM, Blackshear JL, Laupacis A, Kronmal R, Hart RG: Prevalence, age distribution, and gender of patients with atrial fibrillation. Analysis and implications. Arch Intern Med. 1995, 155: 469-473.
Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, Singer DE: Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA. 2001, 285: 2370-2375.
Miyasaka Y, Barnes ME, Gersh BJ, Cha SS, Bailey KR, Abhayaratna WP, Seward JB, Tsang TS: Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation. 2006, 114: 119-125.
Altshuler D, Daly MJ, Lander ES: Genetic mapping in human disease. Science. 2008, 322: 881-888.
Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ: Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA. 2001, 285: 2864-2870.
, : The stroke prevention in atrial fibrillation III study: rationale, design, and patient features. J Stroke Cerebrovasc Dis. 1997, 6: 341-353.
Kopecky SL, Gersh BJ, McGoon MD, Whisnant JP, Holmes DR, Ilstrup DM, Frye RL: The natural history of lone atrial fibrillation. A population-based study over three decades. N Engl J Med. 1987, 317: 669-674.
Chugh SS, Blackshear JL, Shen WK, Hammill SC, Gersh BJ: Epidemiology and natural history of atrial fibrillation: clinical implications. J Am Coll Cardiol. 2001, 37: 371-378.
Fox CS, Parise H, D'Agostino RB, Lloyd-Jones DM, Vasan RS, Wang TJ, Levy D, Wolf PA, Benjamin EJ: Parental atrial fibrillation as a risk factor for atrial fibrillation in offspring. JAMA. 2004, 291: 2851-2855.
Arnar DO, Thorvaldsson S, Manolio TA, Thorgeirsson G, Kristjansson K, Hakonarson H, Stefansson K: Familial aggregation of atrial fibrillation in Iceland. Eur Heart J. 2006, 27: 708-712.
Ellinor PT, Yoerger DM, Ruskin JN, MacRae CA: Familial aggregation in lone atrial fibrillation. Hum Genet. 2005, 118: 179-184.
Brugada R, Tapscott T, Czernuszewicz GZ, Marian AJ, Iglesias A, Mont L, Brugada J, Girona J, Domingo A, Bachinski LL, Roberts R: Identification of a genetic locus for familial atrial fibrillation. N Engl J Med. 1997, 336: 905-911.
Oberti C, Wang L, Li L, Dong J, Rao S, Du W, Wang Q: Genome-wide linkage scan identifies a novel genetic locus on chromosome 5p13 for neonatal atrial fibrillation associated with sudden death and variable cardiomyopathy. Circulation. 2004, 110: 3753-3759.
Chen YH, Xu SJ, Bendahhou S, Wang XL, Wang Y, Xu WY, Jin HW, Sun H, Su XY, Zhuang QN, Yang YQ, Li YB, Liu Y, Xu HJ, Li XF, Ma N, Mou CP, Chen Z, Barhanin J, Huang W: KCNQ1 gain-of-function mutation in familial atrial fibrillation. Science. 2003, 299: 251-254.
Xia M, Jin Q, Bendahhou S, He Y, Larroque MM, Chen Y, Zhou Q, Yang Y, Liu Y, Liu B, Zhu Q, Zhou Y, Lin J, Liang B, Li L, Dong X, Pan Z, Wang R, Wan H, Qiu W, Xu W, Eurlings P, Barhanin J, Chen Y: A Kir2.1 gain-of-function mutation underlies familial atrial fibrillation. Biochem Biophys Res Commun. 2005, 332: 1012-1019.
McNair WP, Ku L, Taylor MR, Fain PR, Dao D, Wolfel E, Mestroni L: SCN5A mutation associated with dilated cardiomyopathy, conduction disorder, and arrhythmia. Circulation. 2004, 110: 2163-2167.
Olson TM, Michels VV, Ballew JD, Reyna SP, Karst ML, Herron KJ, Horton SC, Rodeheffer RJ, Anderson JL: Sodium channel mutations and susceptibility to heart failure and atrial fibrillation. JAMA. 2005, 293: 447-454.
Ellinor PT, Moore RK, Patton KK, Ruskin JN, Pollak MR, Macrae CA: Mutations in the long QT gene, KCNQ1, are an uncommon cause of atrial fibrillation. Heart. 2004, 90: 1487-1488.
Ellinor PT, Petrov-Kondratov VI, Zakharova E, Nam EG, MacRae CA: Potassium channel gene mutations rarely cause atrial fibrillation. BMC Med Genet. 2006, 7: 70-
Damani SB, Topol EJ: Future use of genomics in coronary artery disease. J Am Coll Cardiol. 2007, 50: 1933-1940.
Hirschhorn JN, Daly MJ: Genome-wide association studies for common diseases and complex traits. Nat Rev Genet. 2005, 6: 95-108.
Boerwinkle E, Hixson JE, Hanis CL: Peeking under the peaks: following up genome-wide linkage analyses. Circulation. 2000, 102: 1877-1878.
Altmuller J, Palmer LJ, Fischer G, Scherb H, Wjst M: Genomewide scans of complex human diseases: true linkage is hard to find. Am J Hum Genet. 2001, 69: 936-950.
Frazer KA, Murray SS, Schork NJ, Topol EJ: Human genetic variation and its contribution to complex traits. Nat Rev Genet. 2009, 10: 241-251.
, Frazer KA, Ballinger DG, Cox DR, Hinds DA, Stuve LL, Gibbs RA, Belmont JW, Boudreau A, Hardenbol P, Leal SM, Pasternak S, Wheeler DA, Willis TD, Yu F, Yang H, Zeng C, Gao Y, Hu H, Hu W, Li C, Lin W, Liu S, Pan H, Tang X, Wang J, Wang W, Yu J, Zhang B, Zhang Q, et al.: A second generation human haplotype map of over 3.1 million SNPs. Nature. 2007, 449: 851-861.
Shah G, Brugada R, Gonzalez O, Czernuszewicz G, Gibbs RA, Bachinski L, Roberts R: The cloning, genomic organization and tissue expression profile of the human DLG5 gene. BMC Genomics. 2002, 3: 6-
Ellinor PT, Shin JT, Moore RK, Yoerger DM, MacRae CA: Locus for atrial fibrillation maps to chromosome 6q14-16. Circulation. 2003, 107: 2880-2883.
Hong K, Bjerregaard P, Gussak I, Brugada R: Short QT syndrome and atrial fibrillation caused by mutation in KCNH2. J Cardiovasc Electrophysiol. 2005, 16: 394-396.
Barhanin J, Lesage F, Guillemare E, Fink M, Lazdunski M, Romey G: K(V)LQT1 and lsK (minK) proteins associate to form the I(Ks) cardiac potassium current. Nature. 1996, 384: 78-80.
Wang Q, Curran ME, Splawski I, Burn TC, Millholland JM, VanRaay TJ, Shen J, Timothy KW, Vincent GM, de Jager T, Schwartz PJ, Toubin JA, Moss AJ, Atkinson DL, Landes GM, Connors TD, Keating MT: Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Genet. 1996, 12: 17-23.
Yang Y, Xia M, Jin Q, Bendahhou S, Shi J, Chen Y, Liang B, Lin J, Liu Y, Liu B, Zhou Q, Zhang D, Wang R, Ma N, Su X, Niu K, Pei Y, Xu W, Chen Z, Wan H, Cui J, Barhanin J, Chen Y: Identification of a KCNE2 gain-of-function mutation in patients with familial atrial fibrillation. Am J Hum Genet. 2004, 75: 899-905.
Tsai CT, Lai LP, Hwang JJ, Lin JL, Chiang FT: Molecular genetics of atrial fibrillation. J Am Coll Cardiol. 2008, 52: 241-250.
Moe GK: Evidence for reentry as a mechanism of cardiac arrhythmias. Rev Physiol Biochem Pharmacol. 1975, 72: 55-81.
Hohnloser SH, Crijns HJ, van Eickels M, Gaudin C, Page RL, Torp-Pedersen C, Connolly SJ: Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med. 2009, 360: 668-678.
Chen LY, Ballew JD, Herron KJ, Rodeheffer RJ, Olson TM: A common polymorphism in SCN5A is associated with lone atrial fibrillation. Clin Pharmacol Ther. 2007, 81: 35-41.
Zhang X, Chen S, Yoo S, Chakrabarti S, Zhang T, Ke T, Oberti C, Yong SL, Fang F, Li L, de la Fuente R, Wang L, Chen Q, Wang QK: Mutation in nuclear pore component NUP155 leads to atrial fibrillation and early sudden cardiac death. Cell. 2008, 135: 1017-1027.
Weis K: Regulating access to the genome: nucleocytoplasmic transport throughout the cell cycle. Cell. 2003, 112: 441-445.
Gollob MH, Jones DL, Krahn AD, Danis L, Gong XQ, Shao Q, Liu X, Veinot JP, Tang AS, Stewart AF, Tesson F, Klein GJ, Yee R, Skanes AC, Guiraudon GM, Ebihara L, Bai D: Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation. N Engl J Med. 2006, 354: 2677-2688.
Firouzi M, Ramanna H, Kok B, Jongsma HJ, Koeleman BP, Doevendans PA, Groenewegen WA, Hauer RN: Association of human connexin40 gene polymorphisms with atrial vulnerability as a risk factor for idiopathic atrial fibrillation. Circ Res. 2004, 95: e29-e33.
Juang JM, Chern YR, Tsai CT, Chiang FT, Lin JL, Hwang JJ, Hsu KL, Tseng CD, Tseng YZ, Lai LP: The association of human connexin 40 genetic polymorphisms with atrial fibrillation. Int J Cardiol. 2007, 116: 107-112.
Tsai CT, Lai LP, Lin JL, Chiang FT, Hwang JJ, Ritchie MD, Moore JH, Hsu KL, Tseng CD, Liau CS, Tseng YZ: Renin-angiotensin system gene polymorphisms and atrial fibrillation. Circulation. 2004, 109: 1640-1646.
Hodgson-Zingman DM, Karst ML, Zingman LV, Heublein DM, Darbar D, Herron KJ, Ballew JD, de Andrade M, Burnett JC, Olson TM: Atrial natriuretic peptide frameshift mutation in familial atrial fibrillation. N Engl J Med. 2008, 359: 158-165.
Levin ER, Gardner DG, Samson WK: Natriuretic peptides. N Engl J Med. 1998, 339: 321-328.
Sorbera LA, Morad M: Atrionatriuretic peptide transforms cardiac sodium channels into calcium-conducting channels. Science. 1990, 247: 969-973.
Li D, Shinagawa K, Pang L, Leung TK, Cardin S, Wang Z, Nattel S: Effects of angiotensin-converting enzyme inhibition on the development of the atrial fibrillation substrate in dogs with ventricular tachypacing-induced congestive heart failure. Circulation. 2001, 104: 2608-2614.
Fatini C, Sticchi E, Genuardi M, Sofi F, Gensini F, Gori AM, Lenti M, Michelucci A, Abbate R, Gensini GF: Analysis of minK and eNOS genes as candidate loci for predisposition to non-valvular atrial fibrillation. Eur Heart J. 2006, 27: 1712-1718.
Kato K, Oguri M, Hibino T, Yajima K, Matsuo H, Segawa T, Watanabe S, Yoshida H, Satoh K, Nozawa Y, Yokoi K, Yamada Y: Genetic factors for lone atrial fibrillation. Int J Mol Med. 2007, 19: 933-939.
Gudbjartsson DF, Arnar DO, Helgadottir A, Gretarsdottir S, Holm H, Sigurdsson A, Jonasdottir A, Baker A, Thorleifsson G, Kristjansson K, Palsson A, Blondal T, Sulem P, Backman VM, Hardarson GA, Palsdottir E, Helgason A, Sigurjonsdottir R, Sverrisson JT, Kostulas K, Ng MC, Baum L, So WY, Wong KS, Chan JC, Furie KL, Greenberg SM, Sale M, Kelly P, MacRae CA, et al.: Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature. 2007, 448: 353-357.
Kääb S, Darbar D, van Noord C, Dupuis J, Pfeufer A, Newton-Cheh C, Schnabel R, Makino S, Sinner MF, Kannankeril PJ, Beckmann BM, Choudry S, Donahue BS, Heeringa J, Perz S, Lunetta KL, Larson MG, Levy D, MacRae CA, Ruskin JN, Wacker A, Schömig A, Wichmann HE, Steinbeck G, Meitinger T, Uitterlinden AG, Witteman JC, Roden DM, Benjamin EJ, Ellinor PT: Large scale replication and meta-analysis of variants on chromosome 4q25 associated with atrial fibrillation. Eur Heart J. 2009, 30: 813-819.
Chung MK, Van Wagoner DR, Smith JD, Wirka JD, Topol EJ, Desai MY, Prcela L, Hazen SL, Barnard J: Significant single nucleotide polymorphism associated with atrial fibrillation located on chromosome 4q25 in a whole genome association study and association with left atrial gene expression [abstract]. Circulation. 2008, 118: S_882-
Mommersteeg MT, Hoogaars WM, Prall OW, de Gier-de Vries C, Wiese C, Clout DE, Papaioannou VE, Brown NA, Harvey RP, Moorman AF, Christoffels VM: Molecular pathway for the localized formation of the sinoatrial node. Circ Res. 2007, 100: 354-362.
Mommersteeg MT, Brown NA, Prall OW, de Gier-de Vries C, Harvey RP, Moorman AF, Christoffels VM: Pitx2c and Nkx2-5 are required for the formation and identity of the pulmonary myocardium. Circ Res. 2007, 101: 902-909.
Haissaguerre M, Jais P, Shah DC, Takahashi A, Hocini M, Quiniou G, Garrigue S, Le Mouroux A, Le Metayer P, Clementy J: Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med. 1998, 339: 659-666.
Gretarsdottir S, Thorleifsson G, Manolescu A, Styrkarsdottir U, Helgadottir A, Gschwendtner A, Kostulas K, Kuhlenbäumer G, Bevan S, Jonsdottir T, Bjarnason H, Saemundsdottir J, Palsson S, Arnar DO, Holm H, Thorgeirsson G, Valdimarsson EM, Sveinbjörnsdottir S, Gieger C, Berger K, Wichmann HE, Hillert J, Markus H, Gulcher JR, Ringelstein EB, Kong A, Dichgans M, Gudbjartsson DF, Thorsteinsdottir U, Stefansson K: Risk variants for atrial fibrillation on chromosome 4q25 associate with ischemic stroke. Ann Neurol. 2008, 64: 402-409.
Tayal AH, Tian M, Kelly KM, Jones SC, Wright DG, Singh D, Jarouse J, Brillman J, Murali S, Gupta R: Atrial fibrillation detected by mobile cardiac outpatient telemetry in cryptogenic TIA or stroke. Neurology. 2008, 71: 1696-1701.
Nejentsev S, Walker N, Riches D, Egholm M, Todd JA: Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science. 2009, 324: 387-389.
Murray SS, Topol EJ: Gaining insights in coronary disease genomics. J Am Coll Cardiol. 2008, 52: 385-386.
McCarthy MI, Abecasis GR, Cardon LR, Goldstein DB, Little J, Ioannidis JP, Hirschhorn JN: Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nat Rev Genet. 2008, 9: 356-369.
The authors declare that they have no competing interests.
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Damani, S.B., Topol, E.J. Molecular genetics of atrial fibrillation. Genome Med 1, 54 (2009) doi:10.1186/gm54
- Atrial Fibrillation
- Atrial Natriuretic Peptide
- Nuclear Pore Complex
- Cryptogenic Stroke
- Lone Atrial Fibrillation