Identification of a Genetic Locus for Familial Atrial Fibrillation
Ramon Brugada, M.D., Terry Tapscott, B.S., Grazyna Z. Czernuszewicz, M.S., A.J. Marian, M.D., Anna Iglesias, B.S., Lluis Mont, M.D., Josep Brugada, M.D., Josep Girona, M.D., Anna Domingo, M.D., Linda L. Bachinski, Ph.D., and Robert Roberts, M.D.
Background Atrial fibrillation, the most common sustained cardiac-rhythmdisturbance, affects over 2 million Americans and accounts forone third of all strokes in patients over 65 years of age. Themolecular basis for atrial fibrillation is unknown, and palliativetherapy is used to control the ventricular rate and preventsystemic emboli. We identified a family of 26 members of whom10 had atrial fibrillation that segregated as an autosomal dominantdisease. We subsequently identified two additional familiesin which the disease was linked to the same locus.
Methods We screened the human genome with 300 polymorphic dinucleotide-repeatmarkers using an unconventional strategy of pooling the DNAsamples into two groups (affected and unaffected), which reducedthe sample size by approximately 90 percent, before performinglinkage analysis to map the locus. This made it possible toidentify potential loci within a few weeks.
Results The lod scores for markers D10S569 and D10S607, locatedat 10q22–q24, were 3.60 in Family 1. The disease locusin Families 2 and 3 was also linked to the same markers, withlod scores of 6.02 and 5.35 for markers D10S569 and D10S607,respectively, when data on all three families were combined.Haplotype analysis of the three families showed that the locuswas between D10S1694 and D10S1786, an interval of 11.3 centimorgans.
Conclusions Identification of the gene for familial atrial fibrillationwill help to elucidate the molecular basis of the disease andprovide insights into acquired forms. The strategy of poolingDNA samples for analysis is more time and cost effective thanconventional screening and should accelerate the process ofgene mapping in the future.
Atrial fibrillation, the most common sustained cardiac-rhythmdisturbance,1 affects more than 2 million Americans,2 with anoverall prevalence of 0.89 percent. The prevalence increasesrapidly with age to 2.3 percent between the ages of 40 and 60years and to 5.9 percent over the age of 65.2 Although the initialcourse of atrial fibrillation is often paroxysmal, it almostinvariably progresses to a chronic sustained rhythm disturbancewith manifestations ranging from palpitations to cardiac failure.The most dreaded complication is stroke; atrial fibrillationaccounts for one third of all strokes in patients over the ageof 65.3 Since there is currently no effective means of preventingor eliminating atrial fibrillation, therapy consists of controllingthe ventricular rate and preventing systemic emboli with antiplateletand anticoagulant therapy.4 The emotional and medical burdensimposed by long-term medical therapy and, in many cases, subsequentstroke are immense, with a total annual cost of $9 billion.
The molecular basis of atrial fibrillation has yet to be determined.One approach, which has been successful for metabolic disorders,is to identify the gene responsible for a familial form of thedisease. Familial atrial fibrillation is probably very uncommon,5but we located a small family in Spain in which atrial fibrillationsegregates as an autosomal dominant trait. Only 10 living familymembers were affected; thus, to map the chromosomal locus byconventional genetic-linkage analysis would probably requireanalyzing DNA markers every 5 to 10 centimorgans (cM) throughoutthe human genome. The arduous task of analyzing DNA from eachof the 26 family members for 300 to 600 markers would also bevery costly. Accordingly, we adopted an unconventional strategyof pooling the DNA of the affected family members and comparingthe results of the DNA analysis with those of an analysis ofpooled DNA from unaffected family members at each marker locusto detect differences that would suggest segregation of a particularallele with the disease. This reduced the number of samplesto be analyzed by more than 90 percent and enabled us to identifyfour potential loci within a few weeks.
Methods
Study Families and Diagnosis
We identified a family (Family 1) in which atrial fibrillationappears to be segregating as an autosomal dominant disease withhigh penetrance. The family consists of 26 living members spanningthree generations, of whom 10 have atrial fibrillation. Twoadditional family members are known to have died of complicationsof the disease. We subsequently identified two other small familieswith a total of 17 living members, 9 of whom are affected. Inthese two families (Families 2 and 3) the defect mapped to thesame locus as in the original family. The three pedigrees areshown in Figure 1.
Figure 1. Pedigrees of Three Families with Familial Atrial Fibrillation.
Circles denote female family members, squares male family members, solid symbols affected family members, symbols with a slash deceased family members, and the symbol with a question mark a family member whose disease status has not been determined.
Clinical Evaluation
After providing informed consent according to the guidelinesof Baylor College of Medicine and Methodist Hospital, the subjectswere evaluated by a detailed history taking, physical examination,12-lead electrocardiography, and two-dimensional echocardiography.Criteria for diagnosis were based on the electrocardiographicfindings. Other likely causes of atrial fibrillation in thispopulation — such as hypertension, valvular disease, andthyroid disease — were ruled out at the time of diagnosis.
Preparation of DNA and Pooled Samples
Blood was collected from each member of the three families,DNA was extracted by the salting-out procedure,6 and lymphocyteswere isolated for the development of transformed cell lines.7For the pooled-sample analysis we used blood only from Family1. Equimolar amounts of DNA from 10 affected members (SubjectsII-2, II-3, III-1, III-3, III-5, III-11, IV-6, IV-7, IV-8, andIV-9) were combined into a single sample, as was DNA from 10unaffected family members (Subjects II-1, II-4, II-6, III-4,III-6, III-8, III-9, III-10, III-12, and IV-5). Whenever possible,unaffected siblings and parents of affected subjects were chosento provide samples for the unaffected pool in order to minimizethe allelic differences between the two groups.
Marker Analysis
A total of about 300 polymorphic dinucleotide — (CA)n— repeat markers located approximately 15 to 20 cM apartwere selected on the basis of their polymorphic informationcontent primarily from the genetic maps of Genethon8 or theNational Institutes of Health–Centre d'Etude du PolymorphismeHumain.9 For each microsatellite marker, primers annealing tothe sense strand were end-labeled with [32P]-deoxyadenosinetriphosphate with polynucleotide kinase (Pharmacia), and theDNA was amplified by the polymerase chain reaction under standardconditions for 30 cycles consisting of denaturation at 94°Cfor 45 seconds, annealing at 55°C for 30 seconds, and extensionat 72°C for 30 seconds. Some markers required a higher annealingtemperature. Initial denaturation was carried out at 95°Cfor five minutes. Each 50-µl reaction contained 150 pmolof specific primers, 0.3 U of Taq polymerase (Pharmacia), 200µM 4-deoxynucleoside triphosphate, and 200 ng of genomicDNA for the analysis of either individual or pooled DNA samples.The amplified DNA products were analyzed by electrophoresisthrough 6 percent denaturing polyacrylamide–urea sequencinggels as previously described.10
After the 300 chromosomal markers were amplified from the twopooled DNA samples, the products were loaded side by side ona polyacrylamide gel and then subjected to electrophoresis.The electrophoretic pattern exhibited on the autoradiographby each marker allele amplified from the pooled sample fromthe affected group was visually inspected, and the results werecompared with those of the pooled sample from the unaffectedgroup. The presence of a unique band or a band of greater intensityin the sample from the affected group suggested cosegregationof the marker allele with the disease allele.
Linkage Analysis
Two-point linkage analysis was carried out on a personal computerwith version 5.2 of the Linkage program.11 Multipoint linkageanalysis was conducted on a Vax computer with Fastlink. An autosomaldominant pattern of inheritance was assumed, and penetrancewas set at 99 percent, on the basis of the observed high frequencyof affected persons in sibships at risk in Family 1. The frequenciesof the disease allele and the normal allele were assumed tobe 0.0001 and 0.9999, respectively, and the allele frequenciesof microsatellite markers were arbitrarily assigned a valueof 1/n, where n refers to the number of alleles observed. Sincethe use of incorrect values for linkage parameters can causefalse positive results, positive lod scores were tested forrobustness with respect to variations in penetrance (from 60to 99 percent), variations in the prevalence of phenocopies(from 0 to 5 percent), and marker-allele frequency with theuse of published frequencies, when available, or the frequenciesobserved in this family.
Results
Clinical Characteristics
In Family 1 there were 10 living affected subjects (6 male and4 female) whose age at diagnosis ranged from 2 to 35 years (average,17.8). Nine family members had chronic atrial fibrillation,and one (Subject IV-6) had paroxysmal atrial fibrillation. Threehad dyspnea on exertion (Subjects IV-6, II-2, and III-5), andseven were asymptomatic. Subject III-1 had pericarditis andatrial fibrillation at the time of diagnosis, but since theatrial fibrillation has persisted for 10 years, pericarditiswas not considered the cause. Subject II-8 died of a cerebrovascularaccident at the age of 68. Subject III-2, who was given a diagnosisof paroxysmal atrial fibrillation at the age of 20, died suddenlyat the age of 36; no autopsy was performed. Electrocardioversionwas attempted unsuccessfully in three of those with chronicatrial fibrillation. Subjects II-2 and III-5 had increased leftventricular internal diameters and ventricular ejection fractionsof 51 and 54 percent, respectively. The remainder had no abnormalitieson echocardiography, and the average ejection fraction was 69percent.
In Families 2 and 3, all nine affected subjects had chronicatrial fibrillation, were asymptomatic, and had no echocardiographicabnormalities. The age at diagnosis in these two families rangedfrom 2 to 46 years.
DNA Analysis and Genetic Linkage
The 300 chromosomal markers used to screen the human genomewere amplified from the pooled DNA samples from affected andunaffected subjects; the pooling procedure reduced the numberof samples to be analyzed from 26 to 2. The electrophoreticpattern of the sample from the affected group differed fromthat of the unaffected group for 50 of the 300 marker alleles.These differences, which suggested potential loci for the generesponsible for atrial fibrillation, were identified withina few weeks. A typical example of a difference in a marker allelebetween the pooled samples is shown in Figure 2. In lanes 1and 2 and lanes 3 and 4 of Figure 2, the electrophoretic patternis similar, indicating that the two marker alleles are segregatingat random with respect to the disease allele. In contrast, theintensity of the uppermost allele band in lane 6, showing thesample from the affected group, is greater than the intensityof the corresponding allele in lane 5, showing the sample fromthe unaffected group. A marker allele with greater intensityin the affected group, presumably due to an increased numberof copies of the allele, suggests cosegregation with the disease.
Figure 2. Results of Polyacrylamide-Gel Electrophoresis of Four DNA-Marker Loci Amplified from Pooled DNA.
In lanes 1 and 2 and lanes 3 and 4 the electrophoretic patterns are identical for the markers amplified from the pooled DNA samples from the unaffected and affected groups. The samples shown in lanes 5 and 6 and lanes 7 and 8 show typical differences in band intensity observed between the two groups. The intensity of the lowermost band in lane 8 is much greater than that of the corresponding band in lane 7, reflecting an increase in the number of copies of that allele in the affected group that is consistent with the occurrence of cosegregation of the marker allele and the disease allele.
To confirm or rule out cosegregation, genetic-linkage analysiswas necessary. This required genotyping of DNA from each ofthe 26 members of Family 1 for each of the 50 marker alleles.The resulting lod scores were at least -2 for all but four loci,for which low, positive scores were obtained that were consistentwith the occurrence of cosegregation of the marker allele andthe disease allele. Additional markers located in these fourregions were amplified and analyzed, and the results ruled outthree of these regions (4q, 7q, and 13q), but marker alleles(D10S569 and D10S607) in the region 10q22 cosegregated withthe disease allele, with maximal two-point lod scores of 3.60,indicating genetic linkage. Lod scores for these markers remainedabove 3.0 despite variations in penetrance from 60 to 99 percent.
Since the estimated prevalence of atrial fibrillation in thegeneral population below the age of 40 is less than 0.04 percent2and the nonfamilial causes of atrial fibrillation at this youngage are almost exclusively related to valvular heart diseaseor congenital defects, a phenocopy prevalence of even 1 percentis probably excessive. Nevertheless, lod scores for these markersremained significant even with a phenocopy prevalence of 5 percent.Similarly, lod scores were not sensitive to variations in theestimated frequencies of marker alleles.
We also typed a number of markers in Families 2 and 3 and determinedthat they had the same haplotype on the affected chromosomeas Family 1 for all markers from D10S188 to D10S219, suggestingthat the three families are distantly related. Markers outsidethis interval (D10S581, D10S1694, D10S1786, and D10S1686) wereassociated with different alleles in the other two families.A total of 27 markers were examined in an effort to define theprecise boundaries of the region, but not all these markerswere informative. Lod scores for the four most informative markersare presented in Table 1. Multipoint analyses resulted in apeak lod score of 3.60 between markers D10S569 and D10S607 forFamily 1 alone and 6.17 for all three families combined andcontributed no new information with respect to the locationof the gene for atrial fibrillation.
Table 1. Two-Point Lod Scores for Four Informative Markers Linked to 10q22–q24.
Figure 3, Figure 4, and Figure 5 show the haplotypes for 11informative markers in all three families and the positionsof the recombination events that helped determine the locationof the gene. In Family 1 crossovers were observed between thedisease allele and D10S1786 in Subject III-1 and between thedisease allele and D10S581 in Subject IV-6. Thus, on the basisof haplotype analysis, the gene causing atrial fibrillationin Family 1 lies between D10S581 and D10S1786, an interval ofapproximately 20.2 cM, on chromosome 10q22–q24. Family3 had no crossovers in this region. In Family 2, either SubjectII-2 or Subject II-3 had a crossover between D10S1694 and thedisease allele, further limiting the region to one measuring11.3 cM. Affected members of all three families had identicalalleles for all markers tested from D10S188 through D10S219.Because the haplotype was conserved throughout such a largeregion, we conclude that these three families must be distantlyrelated and have the same mutation at this locus, supportingthe conclusion that the disease gene lies proximal to D10S1786and distal to D10S1694, an interval of 11.3 cM.
Figure 3. Haplotypes and Recombination in Family 1.
Alleles are shown as base-pair sizes in centromere-to-telomere order for markers D10S581, D10S537, D10S1694, D10S188, D10S556, D10S569, D10S607, D10S1677, D10S219, D10S1786, and D10S1686. Alleles in parentheses represent inferred genotypes. For genotypes represented by question marks, no data were available. The most highly conserved haplotypes are assumed, and the chromosomal region cosegregating with the disease locus in each family is represented by the black bar. No attempt has been made to show crossover on the nondiseased chromosome. Circles denote female family members, squares male family members, solid symbols affected family members, and symbols with a slash deceased family members.
Figure 4: Haplotypes and Recombination in Family 2.
See the legend to Figure 3 for an explanation of the symbols. The symbol with a question mark denotes a family member whose disease status has not been determined.
Figure 5: Haplotypes and Recombination in Family 3.
See the legend to Figure 3 for an explanation of the symbols.
Discussion
We identified a small family in whom atrial fibrillation segregatedas an autosomal dominant trait; this family consisted of 26members, 10 of whom were affected and alive at the time of thestudy. Genetic-linkage analysis indicated that the gene responsiblefor atrial fibrillation in this family is located on chromosome10q in the region of 10q22–q24, with two markers havingmaximal lod scores of 3.60. We identified regions containingpotential loci for this gene within a few weeks by comparingthe electrophoretic patterns exhibited by markers amplifiedfrom pooled DNA samples from the affected group with those observedin the pooled DNA samples from the unaffected parents and siblings,rather than by genotyping each marker in all 26 family members.This procedure reduced the number of samples in the genomicscreen by 90 percent. Individual DNA analyses were performedfor only 50 markers (a reduction of approximately 75 percent),resulting in the identification of the locus within a few weeksas opposed to several months to a year. The strategy gives rapidresults and should be particularly useful in small familieswith a high penetrance of the disease gene. Subsequently, weidentified two other families with atrial fibrillation thatwas also linked to 10q22–q24 (combined lod score for allthree families, 6.02). The odds of genetic linkage of the diseasein these families to the region of 10q22–q24 remainedsignificant despite the wide range of values used for the variablesin the linkage analyses — namely, a phenocopy prevalenceof up to 5 percent and penetrance ranging from 60 to 99 percent.This analysis provides the first essential step in the identificationof the responsible molecular defect.
The pooled-sample approach is based on the fact that each DNAmarker has a unique and characteristic distribution of allelefrequencies in the general population. When the DNA is pooledinto two groups (affected and unaffected), each sample containsmany alleles (rather than two, as is the case for a single subject),and thus, the intensity of the electrophoretic bands is dependenton the frequencies with which those alleles are representedin the pool. If a marker allele is segregating at random withrespect to a disease, its distribution in the affected and unaffectedsubjects will be identical. If, on the other hand, a particularmarker allele is cosegregating with the disease allele, thenall the members of the affected pool will share this alleleand DNA analysis will show a band of greater intensity thanin the sample from the unaffected subjects or a unique band.The strategy of using pooled DNA samples to look for differencesin allele distribution has been used to identify the locus ofa recessive disease in a highly inbred population.12 Its lackof use in autosomal dominant diseases is probably due to theexpectation that the inordinately high incidence of differencesbetween affected and unaffected samples would represent falsepositive results. We minimized false positive results in ourstudy by choosing as unaffected subjects in the pooled sampleonly parents and siblings, who were more likely to share alleleswith the affected subjects.
Candidate genes that must be considered in the search for agenetic cause of atrial fibrillation include genes encodingchannel or pore proteins and genes encoding the sympatheticor parasympathetic system that will influence cardiac conductionor automaticity, such as the -adrenergic receptor or signalingproteins. The genes for the -adrenergic receptor (ADRB1)13 and-adrenergic receptor (ADRA2)14 are located on 10q23–q26,as is the gene for G-protein–coupled receptor kinase (GPRK5),15which interacts with adrenergic receptors.
Mapping of the locus for atrial fibrillation provides the informationnecessary to identify the gene. Although atrial fibrillationis commonly associated with acquired heart disease, a substantialproportion of patients, particularly those with an early onsetof disease, have no other forms of heart disease. It remainsto be determined what percentage of the cases of atrial fibrillationin these patients is due to genetic defects. Thus, identificationof the gene and elucidation of the molecular pathogenesis ofatrial fibrillation should not only clarify the mechanism responsiblefor the familial form, but also shed light on the common acquiredforms and eventually lead to more effective therapy. Identificationof the gene and the responsible mutation is required to establishcausality. The incidence of familial atrial fibrillation andthe percentage of cases attributable to the 10q22–q24locus remain to be determined. Nevertheless, families with familialatrial fibrillation can now be screened rapidly for geneticlinkage to the 10q22–q24 region. For families in whichthe disease does not map to 10q22–q24, ruling out thislocus will turn the search to other loci.
Supported in part by grants from the National Heart, Lung, andBlood Institute Specialized Centers of Research (P50-HL313-01);the National Heart, Lung, and Blood Institute Training Centerin Molecular Cardiology (T32-HL-07706); and the American HeartAssociation Texas Affiliate (95R-1191).
We are indebted to Debora Weaver, Anna Zamora, and Che Riversfor their assistance in the preparation of the manuscript.
Source Information
From the Department of Cardiology, Baylor College of Medicine, Houston (R.B., T.T., G.Z.C., A.J.M., A.I., L.L.B., R.R.); the Cardiac Arrhythmia Service, Department of Cardiology, Hospital Clinic, University of Barcelona, Barcelona, Spain (L.M., J.B.); and the Department of Cardiology, Hospital Materno–Infantil Vall d'Hebron, Barcelona, Spain (J.G., A.D.).
Address reprint requests to Dr. Roberts at Baylor College of Medicine, 6550 Fannin, MS SM677, Houston, TX 77030.
References
The National Heart, Lung, and Blood Institute Working Group on Atrial Fibrillation. Atrial fibrillation: current understandings and research imperatives. J Am Coll Cardiol 1993;22:1830-1834. [Abstract]
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. [Abstract]
Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation: a major contributor to stroke in the elderly: the Framingham Study. Arch Intern Med 1987;147:1561-1564. [Abstract]
Albers GW. Atrial fibrillation and stroke: three new studies, three remaining questions. Arch Intern Med 1994;154:1443-1448. [Abstract]
Beyer F, Paul T, Luhmer I, Bertram H, Kallfelz HC. Familiäres idiopathisches Vorhofflimmern mit Bradyarrhythmie. Z Kardiol 1993;82:674-677. [Medline]
Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988;16:1215-1215. [Free Full Text]
Neitzel H. A routine method for the establishment of permanent growing lymphoblastoid cell lines. Hum Genet 1986;73:320-326. [CrossRef][Medline]
Weissenbach J, Gyapay G, Dib C, et al. A second-generation linkage map of the human genome. Nature 1992;359:794-801. [CrossRef][Medline]
NIH/CEPH Collaborative Mapping Group. A comprehensive genetic linkage map of the human genome. Science 1992;258:67-86. [Free Full Text]
Durand JB, Bachinski LL, Bieling LC, et al. Localization of a gene responsible for familial dilated cardiomyopathy to chromosome 1q32. Circulation 1995;92:3387-3389. [Free Full Text]
Ott J. Analysis of human genetic linkage. Rev. ed. Baltimore: Johns Hopkins University Press, 1991.
Scott DA, Carmi R, Elbedour K, Yosefsberg S, Stone EM, Sheffield VC. An autosomal recessive nonsyndromic-hearing-loss locus identified by DNA pooling using two inbred Bedouin kindreds. Am J Hum Genet 1996;59:385-391. [Medline]
Hoehe M, Berrettini W, Leppert M, et al. Genetic mapping of adrenergic receptor genes. Am J Hum Genet 1989;45:Suppl:A143-A143.abstract
Yang-Feng TL, Xue FY, Zhong WW, et al. Chromosomal organization of adrenergic receptor genes. Proc Natl Acad Sci U S A 1990;87:1516-1520. [Free Full Text]
Bullrich F, Druck T, Kunapuli P, et al. Chromosomal mapping of the genes GPRK5 and GPRK6 encoding G protein-coupled receptor kinases GRK5 and GRK6. Cytogenet Cell Genet 1995;70:250-254. [Medline]
Mont, L., Elosua, R., Brugada, J.
(2009). Endurance sport practice as a risk factor for atrial fibrillation and atrial flutter. Europace
11: 11-17
[Abstract][Full Text]
Viviani Anselmi, C, Novelli, V, Roncarati, R, Malovini, A, Bellazzi, R, Bronzini, R, Marchese, G, Condorelli, G, Montenero, A S, Puca, A A
(2008). Association of rs2200733 at 4q25 with atrial flutter/fibrillation diseases in an Italian population. Heart
94: 1394-1396
[Abstract][Full Text]
Hodgson-Zingman, D. M., Karst, M. L., Zingman, L. V., Heublein, D. M., Darbar, D., Herron, K. J., Ballew, J. D., de Andrade, M., Burnett, J. C. Jr., Olson, T. M.
(2008). Atrial Natriuretic Peptide Frameshift Mutation in Familial Atrial Fibrillation. NEJM
359: 158-165
[Abstract][Full Text]
Schoonderwoerd, B. A., Smit, M. D., Pen, L., Van Gelder, I. C.
(2008). New risk factors for atrial fibrillation: causes of 'not-so-lone atrial fibrillation'. Europace
10: 668-673
[Abstract][Full Text]
Molina, L., Mont, L., Marrugat, J., Berruezo, A., Brugada, J., Bruguera, J., Rebato, C., Elosua, R.
(2008). Long-term endurance sport practice increases the incidence of lone atrial fibrillation in men: a follow-up study. Europace
10: 618-623
[Abstract][Full Text]
Darbar, D., Kannankeril, P. J., Donahue, B. S., Kucera, G., Stubblefield, T., Haines, J. L., George, A. L. Jr, Roden, D. M.
(2008). Cardiac Sodium Channel (SCN5A) Variants Associated with Atrial Fibrillation. Circulation
117: 1927-1935
[Abstract][Full Text]
Sinner, M. F., Pfeufer, A., Akyol, M., Beckmann, B.-M., Hinterseer, M., Wacker, A., Perz, S., Sauter, W., Illig, T., Nabauer, M., Schmitt, C., Wichmann, H.-E., Schomig, A., Steinbeck, G., Meitinger, T., Kaab, S.
(2008). The non-synonymous coding IKr-channel variant KCNH2-K897T is associated with atrial fibrillation: results from a systematic candidate gene-based analysis of KCNH2 (HERG). Eur Heart J
29: 907-914
[Abstract][Full Text]
Darbar, D., Hardy, A., Haines, J. L., Roden, D. M.
(2008). Prolonged signal-averaged P-wave duration as an intermediate phenotype for familial atrial fibrillation.. J Am Coll Cardiol
51: 1083-1089
[Abstract][Full Text]
London, B.
(2008). An irregularly irregular inheritance.. J Am Coll Cardiol
51: 1090-1091
[Full Text]
Stephenson, E. A., Berul, C. I.
(2007). Electrophysiological Interventions for Inherited Arrhythmia Syndromes. Circulation
116: 1062-1080
[Full Text]
Fatkin, D., Otway, R., Vandenberg, J. I.
(2007). Genes and Atrial Fibrillation: A New Look at an Old Problem. Circulation
116: 782-792
[Full Text]
Junttila, M. J., Raatikainen, M.J. P., Perkiomaki, J. S., Hong, K., Brugada, R., Huikuri, H. V.
(2007). Familial clustering of lone atrial fibrillation in patients with saddleback-type ST-segment elevation in right precordial leads. Eur Heart J
28: 463-468
[Abstract][Full Text]
Writing Committee Members, , Fuster, V., Ryden, L. E., Cannom, D. S., Crijns, H. J., Curtis, A. B., Ellenbogen, K. A., Halperin, J. L., Le Heuzey, J.-Y., Kay, G. N., Lowe, J. E., Olsson, S. B., Prystowsky, E. N., Tamargo, J. L., Wann, S., ACC/AHA Task Force Members, , Smith, S. C. Jr, Jacobs, A. K., Adams, C. D., Anderson, J. L., Antman, E. M., Halperin, J. L., Hunt, S. A., Nishimura, R., Ornato, J. P., Page, R. L., Riegel, B., ESC Committee for Practice Guidelines, , Priori, S. G., Blanc, J.-J., Budaj, A., Camm, A. J., Dean, V., Deckers, J. W., Despres, C., Dickstein, K., Lekakis, J., McGregor, K., Metra, M., Morais, J., Osterspey, A., Tamargo, J. L., Zamorano, J. L.
(2006). ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: full text: A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Europace
8: 651-745
[Full Text]
Fuster, V., Ryden, L. E., Cannom, D. S., Crijns, H. J., Curtis, A. B., Ellenbogen, K. A., Halperin, J. L., Le Heuzey, J.-Y., Kay, G. N., Lowe, J. E., Olsson, S. B., Prystowsky, E. N., Tamargo, J. L., Wann, S.
(2006). ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation--Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation) Developed in Collaboration With the European Heart Rhythm Association and the Heart Rhythm Society . J Am Coll Cardiol
48: 854-906
[Full Text]
Fuster, V., Ryden, L. E., Cannom, D. S., Crijns, H. J., Curtis, A. B., Ellenbogen, K. A., Halperin, J. L., Le Heuzey, J.-Y., Kay, G. N., Lowe, J. E., Olsson, S. B., Prystowsky, E. N., Tamargo, J. L., Wann, S.
(2006). ACC/AHA/ESC 2006 Guidelines 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 European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation) Developed in Collaboration With the European Heart Rhythm Association and the Heart Rhythm Society . J Am Coll Cardiol
48: e149-e246
[Full Text]
Fuster, V., Ryden, L. E., Cannom, D. S., Crijns, H. J., Curtis, A. B., Ellenbogen, K. A., Halperin, J. L., Le Heuzey, J.-Y., Kay, G. N., Lowe, J. E., Olsson, S. B., Prystowsky, E. N., Tamargo, J. L., Wann, S., ACC/AHA TASK FORCE MEMBERS, , Smith, S. C. Jr, Jacobs, A. K., Adams, C. D., Anderson, J. L., Antman, E. M., Halperin, J. L., Hunt, S. A., Nishimura, R., Ornato, J. P., Page, R. L., Riegel, B., ESC COMMITTEE FOR PRACTICE GUIDELINES, , Priori, S. G., Blanc, J.-J., Budaj, A., Camm, A. J., Dean, V., Deckers, J. W., Despres, C., Dickstein, K., Lekakis, J., McGregor, K., Metra, M., Morais, J., Osterspey, A., Tamargo, J. L., Zamorano, J. L.
(2006). ACC/AHA/ESC 2006 Guidelines 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 European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): Developed in Collaboration With the European Heart Rhythm Association and the Heart Rhythm Society. Circulation
114: e257-e354
[Full Text]
Fuster, V., Ryden, L. E., Cannom, D. S., Crijns, H. J., Curtis, A. B., Ellenbogen, K. A., Halperin, J. L., Le Heuzey, J.-Y., Kay, G. N., Lowe, J. E., Olsson, S. B., Prystowsky, E. N., Tamargo, J. L., Wann, S., ACC/AHA TASK FORCE MEMBERS, , Smith, S. C. Jr, Jacobs, A. K., Adams, C. D., Anderson, J. L., Antman, E. M., Halperin, J. L., Hunt, S. A., Nishimura, R., Ornato, J. P., Page, R. L., Riegel, B., ESC COMMITTEE FOR PRACTICE GUIDELINES, , Priori, S. G., Blanc, J.-J., Budaj, A., Camm, A. J., Dean, V., Deckers, J. W., Despres, C., Dickstein, K., Lekakis, J., McGregor, K., Metra, M., Morais, J., Osterspey, A., Tamargo, J. L., Zamorano, J. L.
(2006). ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation--Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): Developed in Collaboration With the European Heart Rhythm Association and the Heart Rhythm Society. Circulation
114: 700-752
[Full Text]
Authors/Task Force Members, , Fuster, V., Ryden, L. E., Cannom, D. S., Crijns, H. J., Curtis, A. B., Ellenbogen, K. A., Halperin, J. L., Le Heuzey, J.-Y., Kay, G. N., Lowe, J. E., Olsson, S. B., Prystowsky, E. N., Tamargo, J. L., Wann, S., ESC Committee for Practice Guidelines, , Priori, S. G., Blanc, J.-J., Budaj, A., Camm, A. J., Dean, V., Deckers, J. W., Despres, C., Dickstein, K., Lekakis, J., McGregor, K., Metra, M., Morais, J., Osterspey, A., Tamargo, J. L., Zamorano, J. L., ACC/AHA (Practice Guidelines) Task Force Members, , Smith, S. C. Jr, Jacobs, A. K., Adams, C. D., Anderson, J. L., Antman, E. M., Halperin, J. L., Hunt, S. A., Nishimura, R., Ornato, J. P., Page, R. L., Riegel, B.
(2006). ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation executive summary: A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients with Atrial Fibrillation) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Eur Heart J
27: 1979-2030
[Full Text]
Olson, T. M., Alekseev, A. E., Liu, X. K., Park, S., Zingman, L. V., Bienengraeber, M., Sattiraju, S., Ballew, J. D., Jahangir, A., Terzic, A.
(2006). Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation. Hum Mol Genet
15: 2185-2191
[Abstract][Full Text]
Fatini, C., Sticchi, E., Genuardi, M., Sofi, F., Gensini, F., Gori, A. M., Lenti, M., Michelucci, A., Abbate, R., Gensini, G. F.
(2006). Analysis of minK and eNOS genes as candidate loci for predisposition to non-valvular atrial fibrillation. Eur Heart J
27: 1712-1718
[Abstract][Full Text]
Gollob, M. H., Jones, D. L., Krahn, A. D., Danis, L., Gong, X.-Q., Shao, Q., Liu, X., Veinot, J. P., Tang, A. S.L., Stewart, A. F.R., Tesson, F., Klein, G. J., Yee, R., Skanes, A. C., Guiraudon, G. M., Ebihara, L., Bai, D.
(2006). Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation.. NEJM
354: 2677-2688
[Abstract][Full Text]
Arnar, D. O., Thorvaldsson, S., Manolio, T. A., Thorgeirsson, G., Kristjansson, K., Hakonarson, H., Stefansson, K.
(2006). Familial aggregation of atrial fibrillation in Iceland. Eur Heart J
27: 708-712
[Abstract][Full Text]
Podgoreanu, M. V., Mathew, J. P.
(2005). Prophylaxis Against Postoperative Atrial Fibrillation: Current Progress and Future Directions. JAMA
294: 3140-3142
[Full Text]
Podgoreanu, M. V., Schwinn, D. A.
(2005). New Paradigms in Cardiovascular Medicine: Emerging Technologies and Practices: Perioperative Genomics. J Am Coll Cardiol
46: 1965-1977
[Abstract][Full Text]
Shah, M., Akar, F. G., Tomaselli, G. F.
(2005). Molecular Basis of Arrhythmias. Circulation
112: 2517-2529
[Abstract][Full Text]
Zhang, Z., He, Y., Tuteja, D., Xu, D., Timofeyev, V., Zhang, Q., Glatter, K. A., Xu, Y., Shin, H.-S., Low, R., Chiamvimonvat, N.
(2005). Functional Roles of Cav1.3({alpha}1D) Calcium Channels in Atria: Insights Gained From Gene-Targeted Null Mutant Mice. Circulation
112: 1936-1944
[Abstract][Full Text]
Wiesfeld, A. C.P., Hemels, M. E.W., Van Tintelen, J. P., Van den Berg, M. P., Van Veldhuisen, D. J., Van Gelder, I. C.
(2005). Genetic aspects of atrial fibrillation. Cardiovasc Res
67: 414-418
[Abstract][Full Text]
Ehrlich, J. R., Zicha, S., Coutu, P., Hebert, T. E., Nattel, S.
(2005). Atrial fibrillation-associated minK38G/S polymorphism modulates delayed rectifier current and membrane localization. Cardiovasc Res
67: 520-528
[Abstract][Full Text]
McKeown, P. P.
(2005). Introduction: American College of Chest Physicians Guidelines for the Prevention and Management of Postoperative Atrial Fibrillation After Cardiac Surgery. Chest
128: 6S-8S
[Abstract][Full Text]
Temple, J., Frias, P., Rottman, J., Yang, T., Wu, Y., Verheijck, E. E., Zhang, W., Siprachanh, C., Kanki, H., Atkinson, J. B., King, P., Anderson, M. E., Kupershmidt, S., Roden, D. M.
(2005). Atrial Fibrillation in KCNE1-Null Mice. Circ. Res.
97: 62-69
[Abstract][Full Text]
Beery, T. T.
(2005). The Genetics of Cardiac Arrhythmias. Biol Res Nurs
6: 249-261
[Abstract]
Weiss, D. L., Seemann, G., Sachse, F. B., Dössel, O.
(2005). Modelling of short QT syndrome in a heterogeneous model of the human ventricular wall. Europace
7: S105-S117
[Abstract][Full Text]
Oberti, C., Wang, L., Li, L., Dong, J., Rao, S., Du, W., Wang, Q.
(2004). Genome-Wide Linkage Scan Identifies a Novel Genetic Locus on Chromosome 5p13 for Neonatal Atrial Fibrillation Associated With Sudden Death and Variable Cardiomyopathy. Circulation
110: 3753-3759
[Abstract][Full Text]
Page, R. L.
(2004). Newly Diagnosed Atrial Fibrillation. NEJM
351: 2408-2416
[Full Text]
Fox, A. A., Shernan, S. K., Body, S. C.
(2004). Predictive Genomics of Adverse Events After Cardiac Surgery. SEMIN CARDIOTHORAC VASC ANESTH
8: 297-315
[Abstract]
Ellinor, P T, Moore, R K, Patton, K K, Ruskin, J N, Pollak, M R, MacRae, C A
(2004). Mutations in the long QT gene, KCNQ1, are an uncommon cause of atrial fibrillation. Heart
90: 1487-1488
[Full Text]
Lloyd-Jones, D. M., Wang, T. J., Leip, E. P., Larson, M. G., Levy, D., Vasan, R. S., D'Agostino, R. B., Massaro, J. M., Beiser, A., Wolf, P. A., Benjamin, E. J.
(2004). Lifetime Risk for Development of Atrial Fibrillation: The Framingham Heart Study. Circulation
110: 1042-1046
[Abstract][Full Text]
Fox, C. S., Parise, H., D'Agostino, R. B. Sr, Lloyd-Jones, D. M., Vasan, R. S., Wang, T. J., Levy, D., Wolf, P. A., Benjamin, E. J.
(2004). Parental Atrial Fibrillation as a Risk Factor for Atrial Fibrillation in Offspring. JAMA
291: 2851-2855
[Abstract][Full Text]
Delisle, B. P., Anson, B. D., Rajamani, S., January, C. T.
(2004). Biology of Cardiac Arrhythmias: Ion Channel Protein Trafficking. Circ. Res.
94: 1418-1428
[Abstract][Full Text]
Tsai, C.-T., Lai, L.-P., Lin, J.-L., Chiang, F.-T., Hwang, J.-J., Ritchie, M. D., Moore, J. H., Hsu, K.-L., Tseng, C.-D., Liau, C.-S., Tseng, Y.-Z.
(2004). Renin-Angiotensin System Gene Polymorphisms and Atrial Fibrillation. Circulation
109: 1640-1646
[Abstract][Full Text]
Steinberg, J S
(2004). Atrial fibrillation: an emerging epidemic?. Heart
90: 239-240
[Full Text]
Havranek, E. P., Masoudi, F. A.
(2004). What we're talking about when we talk about race. J Am Coll Cardiol
43: 436-437
[Full Text]
Singer, D. E.
(2003). A 60-Year-Old Woman With Atrial Fibrillation. JAMA
290: 2182-2189
[Full Text]
Gaita, F., Giustetto, C., Bianchi, F., Wolpert, C., Schimpf, R., Riccardi, R., Grossi, S., Richiardi, E., Borggrefe, M.
(2003). Short QT Syndrome: A Familial Cause of Sudden Death. Circulation
108: 965-970
[Abstract][Full Text]
Darbar, D., Herron, K. J., Ballew, J. D., Jahangir, A., Gersh, B. J., Shen, W.-K., Hammill, S. C., Packer, D. L., Olson, T. M.
(2003). Familial atrial fibrillation is a genetically heterogeneous disorder. J Am Coll Cardiol
41: 2185-2192
[Abstract][Full Text]
Mestroni, L.
(2003). Genomic medicine and atrial fibrillation. J Am Coll Cardiol
41: 2193-2196
[Full Text]
Ellinor, P. T., Shin, J. T., Moore, R. K., Yoerger, D. M., MacRae, C. A.
(2003). Locus for Atrial Fibrillation Maps to Chromosome 6q14-16. Circulation
107: 2880-2883
[Abstract][Full Text]
Firouzi, M., Groenewegen, W. A.
(2003). Gene polymorphisms and cardiac arrhythmias. Europace
5: 235-242
[Full Text]
Olgin, J. E., Verheule, S.
(2002). Transgenic and knockout mouse models of atrial arrhythmias. Cardiovasc Res
54: 280-286
[Abstract][Full Text]
Shimizu, A., Centurion, O. A.
(2002). Electrophysiological properties of the human atrium in atrial fibrillation. Cardiovasc Res
54: 302-314
[Abstract][Full Text]
Mont, L, Sambola, A, Brugada, J, Vacca, M, Marrugat, J, Elosua, R, Pare, C, Azqueta, M, Sanz, G
(2002). Long-lasting sport practice and lone atrial fibrillation. Eur Heart J
23: 477-482
[Abstract][Full Text]
Camm, A.J.
(2001). Future role of electrical therapy for atrial fibrillation: reality for all?. Eur Heart J Suppl
3: P53-P56
[Abstract]
Decher, N., Uyguner, O., Scherer, C. R, Karaman, B., Yuksel-Apak, M., Busch, A. E, Steinmeyer, K., Wollnik, B.
(2001). hKChIP2 is a functional modifier of hKv4.3 potassium channels: Cloning and expression of a short hKChIP2 splice variant. Cardiovasc Res
52: 255-264
[Abstract][Full Text]
(2001). Guidelines 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 European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to develop guidelines for the management of patients with atrial fibrillation) developed in collaboration with the North American Society of Pacing and Electrophysiology. Eur Heart J
22: 1852-1923
Fuster, V., Ryden, L. E., Asinger, R. W., Cannom, D. S., Crijns, H. J., Frye, R. L., Halperin, J. L., Kay, G. N., Klein, W. W., Levy, S., McNamara, R. L., Prystowsky, E. N., Wann, L. S., Wyse, D. G., Gibbons, R. J., Antman, E. M., Alpert, J. S., Faxon, D. P., Fuster, V., Gregoratos, G., Hiratzka, L. F., Jacobs, A. K., Russell, R. O., Smith, S. C. Jr, Klein, W. W., Alonso-Garcia, A., Blomstrom-Lundqvist, C., De Backer, G., Flather, M., Hradec, J., Oto, A., Parkhomenko, A., Silber, S., Torbicki, A.
(2001). ACC/AHA/ESC guidelines 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 European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation) Developed in Collaboration With the North American Society of Pacing and Electrophysiology. J Am Coll Cardiol
38: 1266-1266
[Full Text]
Falk, R. H.
(2001). Atrial Fibrillation. NEJM
344: 1067-1078
[Full Text]
Allessie, M. A., Boyden, P. A., Camm, A. J., Kleber, A. G., Lab, M. J., Legato, M. J., Rosen, M. R., Schwartz, P. J., Spooner, P. M., Van Wagoner, D. R., Waldo, A. L.
(2001). Pathophysiology and Prevention of Atrial Fibrillation. Circulation
103: 769-777
[Full Text]
Chugh, S. S., Blackshear, J. L., Shen, W.-K., Hammill, S. C., Gersh, B. J.
(2001). Epidemiology and natural history of atrial fibrillation: clinical implications. J Am Coll Cardiol
37: 371-378
[Abstract][Full Text]
Meurling, C. J., Waktare, J. E. P., Holmqvist, F., Hedman, A., Camm, A. J., Olsson, S. B., Malik, M.
(2001). Diurnal variations of the dominant cycle length of chronic atrial fibrillation. Am. J. Physiol. Heart Circ. Physiol.
280: H401-H406
[Abstract][Full Text]
Roberts, R.
(2000). A perspective: the new millennium dawns on a new paradigm for cardiology--molecular genetics. J Am Coll Cardiol
36: 661-667
[Abstract][Full Text]
Alpert, J.S.
(2000). Atrial fibrillation: a growth industry in the 21st century. Eur Heart J
21: 1207-1208
Ezekowitz, M. D., Levine, J. A.
(1999). Preventing Stroke in Patients With Atrial Fibrillation. JAMA
281: 1830-1835
[Abstract][Full Text]
Yue, L., Melnyk, P., Gaspo, R., Wang, Z., Nattel, S.
(1999). Molecular Mechanisms Underlying Ionic Remodeling in a Dog Model of Atrial Fibrillation. Circ. Res.
84: 776-784
[Abstract][Full Text]
Priori, S. G., Barhanin, J., Hauer, R. N. W., Haverkamp, W., Jongsma, H. J., Kleber, A. G., McKenna, W. J., Roden, D. M., Rudy, Y., Schwartz, K., Schwartz, P. J., Towbin, J. A., Wilde, A. M.
(1999). Genetic and Molecular Basis of Cardiac Arrhythmias: Impact on Clinical Management Parts I and II. Circulation
99: 518-528
[Abstract][Full Text]
Priori, S.G., Barhanin, J., Hauer, R.N.W., Haverkamp, W., Jongsma, H.J., Kleber, A.G., McKenna, W.J., Roden, D.M., Rudy, Y., Schwartz, K., Schwartz, P.J., Towbin, J.A., Wilde, A.
(1999). Genetic and molecular basis of cardiac arrhythmias: Impact on clinical management. Eur Heart J
20: 174-195
PETERS, N. S
(1998). Atrial fibrillation: towards an understanding of initiation, perpetuation, and specific treatment. Heart
80: 533-534
[Full Text]
Klein, M. L., Schultz, D. W., Edwards, A., Matise, T. C., Rust, K., Berselli, C. B., Trzupek, K., Weleber, R. G., Ott, J., Wirtz, M. K., Acott, T. S.
(1998). Age-related Macular Degeneration: Clinical Features in a Large Family and Linkage to Chromosome 1q. Arch Ophthalmol
116: 1082-1088
[Abstract][Full Text]
Colatsky, T. J.
(1998). Controlling Cardiac Arrhythmias: New Drugs in Development and Insights From Molecular Biology. J CARDIOVASC PHARMACOL THER
3: 337-341
MacRae, C. A., Roberts, R.
(1997). Familial Atrial Fibrillation. NEJM
337: 350-350
[Full Text]
(1997). A Genetic Locus for Familial Atrial Fibrillation. Journal Watch Cardiology
1997: 4-4
[Full Text]
Allessie, M. A.
(1997). Is Atrial Fibrillation Sometimes a Genetic Disease?. NEJM
336: 950-952
[Full Text]
-deoxyadenosine triphosphate with polynucleotide kinase (Pharmacia), and the DNA was amplified by the polymerase chain reaction under standard conditions for 30 cycles consisting of denaturation at 94°C for 45 seconds, annealing at 55°C for 30 seconds, and extension at 72°C for 30 seconds. Some markers required a higher annealing temperature. Initial denaturation was carried out at 95°C for five minutes. Each 50-µl reaction contained 150 pmol of specific primers, 0.3 U of Taq polymerase (Pharmacia), 200 µM 4-deoxynucleoside triphosphate, and 200 ng of genomic DNA for the analysis of either individual or pooled DNA samples. The amplified DNA products were analyzed by electrophoresis through 6 percent denaturing polyacrylamide–urea sequencing gels as previously described.10 
-adrenergic receptor or signaling proteins. The genes for the 
-adrenergic receptor (ADRA2)14 are located on 10q23–q26, as is the gene for G-protein–coupled receptor kinase (GPRK5),15 which interacts with adrenergic receptors. 
Previous
