Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Common variants in KCNN3 are associated with lone atrial fibrillation

Abstract

Atrial fibrillation (AF) is the most common sustained arrhythmia. Previous studies have identified several genetic loci associated with typical AF. We sought to identify common genetic variants underlying lone AF. This condition affects a subset of individuals without overt heart disease and with an increased heritability of AF. We report a meta-analysis of genome-wide association studies conducted using 1,335 individuals with lone AF (cases) and 12,844 unaffected individuals (referents). Cases were obtained from the German AF Network, Heart and Vascular Health Study, the Atherosclerosis Risk in Communities Study, the Cleveland Clinic and Massachusetts General Hospital. We identified an association on chromosome 1q21 to lone AF (rs13376333, adjusted odds ratio = 1.56; P = 6.3 × 10−12), and we replicated this association in two independent cohorts with lone AF (overall combined odds ratio = 1.52, 95% CI 1.40–1.64; P = 1.83 × 10−21). rs13376333 is intronic to KCNN3, which encodes a potassium channel protein involved in atrial repolarization.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Manhattan plot of meta-analysis results for genome-wide association to lone AF.
Figure 2: Regional plot for locus on chromosome 1 associated with lone atrial fibrillation.

Similar content being viewed by others

Accession codes

Accessions

NCBI Reference Sequence

References

  1. Fuster, V. et al. 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 (2006).

    Article  Google Scholar 

  2. Jahangir, A. et al. Long-term progression and outcomes with aging in patients with lone atrial fibrillation: a 30-year follow-up study. Circulation 115, 3050–3056 (2007).

    Article  Google Scholar 

  3. Ellinor, P.T., Yoerger, D.M., Ruskin, J.N. & MacRae, C.A. Familial aggregation in lone atrial fibrillation. Hum. Genet. 118, 179–184 (2005).

    Article  Google Scholar 

  4. Fox, C.S. et al. Parental atrial fibrillation as a risk factor for atrial fibrillation in offspring. J. Am. Med. Assoc. 291, 2851–2855 (2004).

    Article  CAS  Google Scholar 

  5. Arnar, D.O. et al. Familial aggregation of atrial fibrillation in Iceland. Eur. Heart J. 27, 708–712 (2006).

    Article  Google Scholar 

  6. Gudbjartsson, D.F. et al. Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature 448, 353–357 (2007).

    Article  CAS  Google Scholar 

  7. Benjamin, E.J. et al. Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry. Nat. Genet. 41, 879–881 (2009).

    Article  CAS  Google Scholar 

  8. Gudbjartsson, D.F. et al. A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke. Nat. Genet. 41, 876–878 (2009).

    Article  CAS  Google Scholar 

  9. Kozlowski, D. et al. Lone atrial fibrillation—what do we know? Heart published online, doi:10.1136/hrt.2009.176321 (26 August 2009).

  10. K, M. et al. Small-conductance, calcium-activated potassium channels from mammalian brain. Science 273, 1709–1714 (1996).

    Article  Google Scholar 

  11. Xu, Y. et al. Molecular identification and functional roles of a Ca2+-activated K+ channel in human and mouse hearts. J. Biol. Chem. 278, 49085–49094 (2003).

    Article  CAS  Google Scholar 

  12. Tuteja, D. et al. Differential expression of small-conductance Ca2+-activated K+ channels SK1, SK2, and SK3 in mouse atrial and ventricular myocytes. Am. J. Physiol. Heart Circ. Physiol. 289, H2714–H2723 (2005).

    Article  CAS  Google Scholar 

  13. Ozgen, N. et al. Early electrical remodeling in rabbit pulmonary vein results from trafficking of intracellular SK2 channels to membrane sites. Cardiovasc. Res. 75, 758–769 (2007).

    Article  CAS  Google Scholar 

  14. Nattel, S. New ideas about atrial fibrillation 50 years on. Nature 415, 219–226 (2002).

    Article  CAS  Google Scholar 

  15. Zhang, Q. et al. Functional roles of a Ca2+-activated K+ channel in atrioventricular nodes. Circ. Res. 102, 465–471 (2008).

    Article  CAS  Google Scholar 

  16. Monaghan, A.S. et al. The SK3 subunit of small conductance Ca2+-activated K+ channels interacts with both SK1 and SK2 subunits in a heterologous expression system. J. Biol. Chem. 279, 1003–1009 (2004).

    Article  CAS  Google Scholar 

  17. Taylor, M.S. et al. Altered expression of small-conductance Ca2+-activated K+ (SK3) channels modulates arterial tone and blood pressure. Circ. Res. 93, 124–131 (2003).

    Article  CAS  Google Scholar 

  18. International HapMap Consortium. The International HapMap Project. Nature 426, 789–796 (2003).

  19. Newton-Cheh, C. et al. Genome-wide association study identifies eight loci associated with blood pressure. Nat. Genet. 41, 666–676 (2009).

    Article  CAS  Google Scholar 

  20. Johnson, A.D. et al. SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap. Bioinformatics 24, 2938–2939 (2008).

    Article  CAS  Google Scholar 

  21. Kaab, S. et al. Large scale replication and meta-analysis of variants on chromosome 4q25 associated with atrial fibrillation. Eur. Heart J. 30, 813–819 (2009).

    Article  Google Scholar 

  22. Wichmann, H.E., Gieger, C. & Illig, T. KORA-gen–resource for population genetics, controls and a broad spectrum of disease phenotypes. Gesundheitswesen 67 (Suppl. 1), S26–S30 (2005).

    Article  Google Scholar 

  23. Dawber, T.R., Meadors, G.F. & Moore, F.E. Jr. Epidemiological approaches to heart disease: the Framingham Study. Am. J. Public Health Nations Health 41, 279–281 (1951).

    Article  CAS  Google Scholar 

  24. Kannel, W.B., Feinleib, M., McNamara, P.M., Garrison, R.J. & Castelli, W.P. An investigation of coronary heart disease in families. The Framingham offspring study. Am. J. Epidemiol. 110, 281–290 (1979).

    Article  CAS  Google Scholar 

  25. Splansky, G.L. et al. The Third Generation Cohort of the National Heart, Lung, and Blood Institute's Framingham Heart Study: design, recruitment, and initial examination. Am. J. Epidemiol. 165, 1328–1335 (2007).

    Article  Google Scholar 

  26. Heckbert, S.R., Li, G., Cummings, S.R., Smith, N.L. & Psaty, B.M. Use of alendronate and risk of incident atrial fibrillation in women. Arch. Intern. Med. 168, 826–831 (2008).

    Article  CAS  Google Scholar 

  27. Fried, L.P. et al. The Cardiovascular Health Study: design and rationale. Ann. Epidemiol. 1, 263–276 (1991).

    Article  CAS  Google Scholar 

  28. Anonymous. The Atherosclerosis Risk in Communities (ARIC) Study: design and objectives. The ARIC investigators. Am. J. Epidemiol. 129, 687–702 (1989).

  29. Darbar, D., Motsinger, A.A., Ritchie, M.D., Gainer, J.V. & Roden, D.M. Polymorphism modulates symptomatic response to antiarrhythmic drug therapy in patients with lone atrial fibrillation. Heart Rhythm 4, 743–749 (2007).

    Article  Google Scholar 

  30. Servin, B. & Stephens, M. Imputation-based analysis of association studies: candidate regions and quantitative traits. PLoS Genet. 3, e114 (2007).

    Article  Google Scholar 

  31. Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

    Article  CAS  Google Scholar 

  32. Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

    Article  CAS  Google Scholar 

  33. de Bakker, P.I. et al. Practical aspects of imputation-driven meta-analysis of genome-wide association studies. Hum. Mol. Genet. 17, R122–R128 (2008).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Acknowledgements are contained in the Supplementary Note.

Author information

Authors and Affiliations

Authors

Contributions

Study concept and design: P.T.E., K.L.L., N.L.G., A.P., M.K.C., A.A., J.C.M.W., D.E.A., E.J.B., S.R.H. and S.K.

Acquisition of data: P.T.E., K.L.L., N.L.G., A.P., A.A., M.K.C., M.F.S., P.I.W.d.B., M.M., S.A.L., E.F., D.D., N.L.S., J.D.S., R.B.S., E.Z.S., K.M.R., D.R.V.W., B.-M.B, C.v.N., K.W., G.B.E., J.I.R., S.L.H., G.S., A.V.S., L.J.L., T.B.H., S.M., M.N., D.J.M., S.P., T.E., S.M., C.N.-C., M.L., S.M., K.W., T.J.W., W.H.L.K., E.B., V.G., B.M.P., J.C.M.W., J.B., D.E.A., E.J.B., S.R.H. and S.K.

Analysis and interpretations of data: K.L.L., N.L.G., A.P., M.M., J.B., D.E.A. and K.W.

Drafting of the manuscript: P.T.E., K.L.L., E.J.B., S.R.H. and S.K.

Critical revision of the manuscript for important intellectual content: K.L.L., N.L.G., A.P., A.A., M.K.C., M.F.S., P.I.W.d.B., M.M., S.A.L., E.F., D.D., N.L.S., J.D.S., R.B.S., E.Z.S., K.M.R., D.R.V.W., B.-M.B., C.v.N., K.W., G.B.E., S.L.H., G.S., A.V.S., L.J.L., T.B.H., S.M., M.M.N., D.J.M., S.P., T.E., A.K., S.M., C.N.-C., M.L., S.M.,T.J.W., W.H.L.K., R.S.V., M.N., C.A.M., B.H.C.S., A.H., A.G.U., D.L., E.B., A.M., E.J.T., A.C., V.G., B.M.P., D.M.R., T.M., H.-E.W., J.C.M.W., J.B., D.E.A., E.J.B. and S.R.H.

Statistical analysis: K.L.L., N.L.G., A.P., M.M., J.B., D.E.A. and K.W.

Obtained funding: P.T.E., A.P., A.A., M.K.C., M.F.S., P.I.W.d.B., M.M., S.A.L., E.F., N.L.S., J.D.S., K.M.R., D.R.V.W., J.I.R., S.L.H., S.M., B.H.Ch.S., A.H., A.G.U., D.L., E.B., A.M., E.J.T., A.C., V.G., B.M.P., D.M.R., T.M., J.C.M.W., J.B., D.E.A., E.J.B., S.R.H. and S.K.

Study supervision: P.T.E., K.L.L., N.L.G., A.P., A.A., M.K.C., M.F.S., J.C.M.W., J.B., D.E.A., E.J.B., S.R.H. and S.K.

P.T.E., K.L.L., N.L.G., A.P., A.A., M.K.C., M.F.S., J.C.M.W., J.B., D.E.A., E.J.B., S.R.H. and S.K. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Corresponding authors

Correspondence to Patrick T Ellinor or Stefan Kääb.

Ethics declarations

Competing interests

A.C. is a paid member of the Scientific Advisory Board of Affymetrix, a role that is managed by the Committee on Conflict of Interest of the Johns Hopkins University School of Medicine.

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Tables 1–3 and Supplementary Figures 1 and 2 (PDF 998 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ellinor, P., Lunetta, K., Glazer, N. et al. Common variants in KCNN3 are associated with lone atrial fibrillation. Nat Genet 42, 240–244 (2010). https://doi.org/10.1038/ng.537

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.537

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing