EDITORIAL

Recent breakthroughs in

the genetics of atrial

fibrillation A trial fibrillation (AF) is the most common arrhythmia. Although more

prevalent in patients with heart disease and advanced age, atrial fibrillation also affects many, often young, patients with structurally normal hearts.' Better understanding of the arrhythmogenesis of AF may lead to more effective treatment and, thereby, reduction of its morbidity and mortality. In 1997, Brugada and coworkers were the first to publish a genetic analysis in patients with familial AF showing a clear linkage to a locus on the long arm of chromosome 10.2 It is now becoming clear that familial AF is a genetically heterogeneous disorder.' Chen and coworkers published a study in Science constituting an important step in better understanding the mechanism underlying lone atrial fibrillation.3 They described a four-generation family from China with autosomal dominant hereditary atrial fibrillation in structurally normal hearts. Sixteen family members were affected. Linkage analysis by means of microsatelite whole-genome screening identified a locus on the short arm ofchromosome 11 (LOD score 4.55). In this region the KCNQ1 gene is present, which encodes the pore-forming unit of a K+ channel (IKS) and which has previously been shown to be causally involved in the long-QT syndrome (type 1). By sequence analysis Chen et al. discovered a missense mutation (S140G) in the KCNQ1 coding region of all affected family members. This mutation was absent in unaffected family members as well as in 188 healthy controls. The authors elegantly showed the electrophysiological consequences by expressing the S140G mutant and the wildtype in an artificial cell-expression system and measuring altered ion channel properties by whole-cell patch-clamping. In coexpression with small subunits from the KCNE family (without which KCNQ1 cannot form functional channels), S140G mutation dramatically modified kinetic and gating properties. The crucial resulting effect of the KCNQI mutation is a gain of function of the IKS channel, which leads to a shortening of the action potential duration and refractory period. Obviously, these alterations facilitate the initiation and continuation of atrial fibrillation. Interestingly, in affected individuals QTc was not shorter compared with controls. This is probably caused by compensatory mechanisms in the ventricle, since differences in the assortment of ion channels exist between atria and ventricles. The KCNQ1 gene was previously shown to be involved in ventricular arrhythmogenesis as loss of function mutations in this gene are known to cause the long-QT syndrome type 1. Now it has been clearly evidenced that a gain of function mutation may underlie lone atrial fibrillation. In another study published in Nature, Mohler et al. showed that a mutation in the gene encoding ankyrin-B, which, interestingly enough, is not an ion channel, causes a variety of arrhythmias in structurally normal hearts.' In a large family long-QT syndrome type 4, sinus node dysfimction and AF were linked to a loss of function mutation in the ankyrin-B gene leading to a reduced routing of Na+/K+ ATPase, Na+/Ca2+ exchanger and inositol-1,4,5,-triphophate receptors to the T-tubule region in the cardiomyocytes. The authors clearly demonstrated that due to these alterations intracellular Ca2+ concentration is elevated, which, in itself, is a paramount arrhythmogenic factor.

Netherlands Heart Journal, Volume 11, Number 10, October 2003

385

Editorial

Also, in patients with structural heart disease genetic factors may predispose to the occurrence of atrial fibrillation. Based on a case-control study in w 216 patients from Taiwan, it is likely that polymorphisms in the minK-gene, encoding the small -subunit of Is, are associated with an increased risk for atrial fibrillation in patients with structural heart disease.6 In general, however, polymorphism studies should be interpreted with caution, Tel.: +31-33422 9900 because associations between common genetic variants and common Fec +313342299 22 E-mail: nni*l'ladsct.nl phenotypes as found within certain sets of patients are often overrated as causative relationships. ISBN 0929-7456 Following the unraveling of many ventricular arrhythmia syndromes,7 genetic research has now identified causative genes in familial atrial fibrillation. Moreover, genetic predisposition might be involved in atrial fibrillation in structurally abnormal hearts. To what extent these new .~~~~~~~~01 .Amm~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ findings may affect treatment of cardiac patients remains largely speculative. it already seems obvious that the development of specific ISHowever, II NO 0 ^ blockers may provide therapeutic benefit to AF patients with the KCNQ1 PLdSW.WmUW -. mutation. Molecular genetic research in cardiovascular disease is progressing at a very fast pace. In our opinion this expansion offundamental knowledge will inevitably influence future cardiac care not only for rare syndromes but also for common arrhythmias. U

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Acknowledgement NHS (project 2001 D019) is gratefully acknowledged for their financial support. mcuflarflwl, asahi puSOroWdv forcoI bt'4m

L.R.C Dekker. A.A.M. Wilde The Experimental and Molecular Cardiology Group, Academic Medical Centre, Amsterdam.

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Darbar D, Herron KJ, Ballew JD, Jahangir A, Gersh BJ, Shen W-K, et al. Familial atrial fibrillation is a genetically heterogeneous disorder. JACC2003;41:2185-92. Brugada R, Tapscott T, Czemuszewicz MS, Marian AJ, Iglesias A, Mont L, et al. Identification of a genetic locus for familial atrial fibrillation. NEnglJMed 1997;336:905-11. Chen YH, Xu SJ, Bendahhou S, Wang XL, Wang Y, Xu WY, et al. KCNQ1 gain-of-function mutation in familial atrial fibrillation. Science 2003;299:251-4. Ellinor PT, Shin JT, Moore RK, Yoerger DM, MacRay CA. Locus for atrial fibrillation maps to chromosome 6q14-16. Circulation 2003;107:2880-3 Mohler PJ, Schott JJ, Gramolini AO, Dilly KW, Guatimosim S, duBell WH, et al. AnkyrinB mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death. Nature 2003;421:634-9. Lai LP, Su MJ,Yeh HM, Lin JL, Chiang FT, Hwang JJ, et al. Association ofthe human minK gene 38G allele with atrial fibrillation: Evidence of possible genetic control on the pathogenesis of atrial fibrillation. Am HeartJ2002;144:485-90. Wilde AAM, Tan HL, Bezzina C. Familial primary arrhythmia syndromes. Nice to know or need to know. Neth HeartJ2002;10:225-7.

Netherlands Heart Joumal, Volume 11, Number 10, October 2003

Recent breakthroughs in the genetics of atrial fibrillation.

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