European Heart Journal Advance Access published online on January 13, 2009
European Heart Journal, doi:10.1093/eurheartj/ehn578
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Large scale replication and meta-analysis of variants on chromosome 4q25 associated with atrial fibrillation
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1 Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-University, Munich, Germany
2 Cardiology Division, Vanderbilt University School of Medicine, 2215B Garland Avenue, Room 1285A, Nashville, TN 37232, USA
3 Department of Epidemiology, Erasmus Medical Center, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands
4 Dutch Medicines Evaluation Board, The Hague, The Netherlands
5 Department of Biostatistics, School of Public Health, Boston University, Boston, MA, USA
6 National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA
7 Institute of Human Genetics, TU München, Klinikum Rechts der Isar, Trogerstr. 32, D-81675 München, Germany
8 Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany
9 Cardiology Division, Massachusetts General Hospital, Boston, MA, USA
10 Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Boston, MA, USA
11 Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
12 Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN, USA
13 Institute of Medical Informatics, Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany
14 Department of Mathematics and Statistics, Boston University, Boston, MA, USA
15 Center for Population Studies, National Heart, Lung, and Blood Institute, Bethesda, MD, USA
16 Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, MA, USA
17 Universitätsklinik für Kinder- und Jugendmedizin, Tübingen, Germany
18 Deutsches Herzzentrum München, Klinik an der Technischen Universität München, Klinik für Kardiologie, Lazarettstraße 36, D- 80636 München, Germany
19 IBE-Chair of Epidemiology, Ludwig-Maximilians-University and Institute of Epidemiology, Helmholtz Center Munich, Germany
20 Department of Internal Medicine and Epidemiology, Erasmus MC, Rotterdam, The Netherlands
21 Department of Epidemiology, School of Public Health, Boston University, Boston, MA, USA
22 Cardiology and Preventive Medicine Division, Evans Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA
Received 23 May 2008; revised 5 November 2008; accepted 4 December 2008.
* Corresponding author. Tel: +1 617 724 8729, Fax: +1 617 726 5806, Email: pellinor{at}partners.org
Aims: A recent genome-wide association study identified a haplotype block on chromosome 4q25 associated with atrial fibrillation (AF). We sought to replicate this association in four independent cohorts.
Methods and results: The Framingham Heart Study and Rotterdam Study are community-based longitudinal studies. The Vanderbilt AF Registry and German AF Network (AFNet) are case–control studies. Participants with AF (n = 3508) were more likely to be male and were older than referent participants (n = 12 173; Framingham 82 ± 10 vs. 71 ± 13 years; Rotterdam 73 ± 8 vs. 69 ± 9 years; Vanderbilt 54 ± 14 vs. 57 ± 14 years; AFNet 62 ± 12 vs. 49 ± 14 years). Single nucleotide polymorphism (SNP) rs2200733 was associated with AF in all four cohorts, with odds ratios (ORs) ranging from 1.37 in Rotterdam [95% confidence interval (CI) 1.18–1.59; P = 3.1 x 10–5] to 2.52 in AFNet (95% CI 2.22–2.8; P = 1.8 x 10–49). There also was a significant association between AF and rs10033464 in Framingham (OR 1.34; 95% CI 1.03–1.75; P = 0.031) and AFNet (OR 1.30; 95% CI 1.13–1.51; P = 0.0002), but not Vanderbilt (OR 1.16; 95% CI 0.86–1.56; P = 0.33). A meta-analysis of the current and prior AF studies revealed an OR of 1.90 (95% CI 1.60–2.26; P = 3.3 x 10–13) for rs2200733 and of 1.36 (95% CI 1.26–1.47; P = 6.7 x 10–15) for rs10033464.
Conclusion: The non-coding SNPs rs2200733 and rs10033464 are strongly associated with AF in four cohorts of European descent. These results confirm the significant relations between AF and intergenic variants on chromosome 4.
Key Words: Atrial fibrillation • Genetics • Arrhythmia • Polymorphism • Meta-analysis
These authors contributed equally to this study.
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