Common Variants in KCNN3 are Associated with Lone AF August 3, 2010

Editor’s Note: Dr. Peng-Sheng Chen, MD, Professor of Medicine at the The Krannert Institute of Cardiology, Indiana University, has agreed to serve as a blogger on EP Insights. In his posts, Dr. Chen will highlight and comment on new studies that affect the heart rhythm community.

Common variants in KCNN3 are associated with lone atrial fibrillation
Ellinor, et al (Nat Genet: 2010;42:240, PMID: 20173747) sought to identify common genetic variants underlying lone atrial fibrillation (AF). This condition affects a subset of individuals without overt heart disease and with an increased heritability of AF.

The authors report a meta-analysis of genome-wide association studies conducted using 1,335 individuals with lone AF (cases) and 12,844 unaffected individuals (referents). They identified an association on chromosome 1q21 to lone AF (rs13376333, adjusted odds ratio = 1.56; P = 6.3 x 10(-12)), and 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 x 10(-21)). rs13376333 is intronic to KCNN3.

In conclusion, the authors identified a new locus for lone AF at the calcium activated potassium channel gene, KCNN3. Future studies will seek to determine the mechanistic links between genetic variation at this locus and AF.

Comments: The small-conductance calcium-activated potassium (SK) channels are first discovered in the brain.¹ Rapid activation of the neurons cause intracellular calcium accumulation, which activates this potassium channel and produces afterhyperpolarization immediately following neural action potentials. This spike-frequency adaptation protects the cell from the deleterious effects of continuous tetanic activity and is essential for normal neurotransmission.² 

Seminal studies from several laboratories show that SK channels are also expressed in cardiac cells, more so in the atria than in the ventricles.^3-9 It is possible that activation of this channel may occur during atrial tachycardia or fibrillation, and produce action potential duration shortening and help perpetuate the arrhythmia. The importance of this channel in the ventricles remains unclear.⁶ SK channels have several subtypes. The study of Ellinor et al was the first to show that the gene encoding subtype SK3 (KCNN3) is associated with lone atrial fibrillation in humans.

As stated in the authors’ conclusions, more studies will be needed to determine the mechanistic links between genetic variation at this locus and AF.

References

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2. Bond CT, Maylie J, Adelman JP. Small-conductance calcium-activated potassium channels. Ann N Y Acad Sci. 1999;868:370-378.

3.  Xu Y, Tuteja D, Zhang Z, Xu D, Zhang Y, Rodriguez J, Nie L, Tuxson HR, Young JN, Glatter KA, Vazquez AE, Yamoah EN, Chiamvimonvat N. Molecular identification and functional roles of a Ca(2+)-activated K+ channel in human and mouse hearts. J.Biol.Chem. 2003;278(49):49085-49094.

4.  Li N, Timofeyev V, Tuteja D, Xu D, Lu L, Zhang Q, Zhang Z, Singapuri A, Albert TR, Rajagopal AV, Bond CT, Periasamy M, Adelman J, Chiamvimonvat N. Ablation of a Ca2+-activated K+ channel (SK2 channel) results in action potential prolongation in atrial myocytes and atrial fibrillation. J.Physiol. 2009;587(Pt 5):1087-1100.

5.  Ozgen N, Dun W, Sosunov EA, Anyukhovsky EP, Hirose M, Duffy HS, Boyden PA, Rosen MR. Early electrical remodeling in rabbit pulmonary vein results from trafficking of intracellular SK2 channels to membrane sites. Cardiovasc.Res. 2007;75(4):758-769.

6. Nagy N, Szuts V, Horvath Z, Seprenyi G, Farkas AS, Acsai K, Prorok J, Bitay M, Kun A, Pataricza J, Papp JG, Nanasi PP, Varro A, Toth A. Does small-conductance calcium-activated potassium channel contribute to cardiac repolarization? J.Mol.Cell Cardiol. 2009;47(5):656-663.

7.  Chandler NJ, Greener ID, Tellez JO, Inada S, Musa H, Molenaar P, DiFrancesco D, Baruscotti M, Longhi R, Anderson RH, Billeter R, Sharma V, Sigg DC, Boyett MR, Dobrzynski H. Molecular architecture of the human sinus node: insights into the function of the cardiac pacemaker. Circulation. 2009;119(12):1562-1575.

8. Zhang Q, Timofeyev V, Lu L, Li N, Singapuri A, Long MK, Bond CT, Adelman JP, Chiamvimonvat N. Functional roles of a Ca2+-activated K+ channel in atrioventricular nodes. Circ Res. 2008;102(4):465-471.

9. Tuteja D, Xu D, Timofeyev V, Lu L, Sharma D, Zhang Z, Xu Y, Nie L, Vazquez AE, Young JN, Glatter KA, Chiamvimonvat N. 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. 2005;289(6):H2714-2723.