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Genetics of Arrhythmia: Disease Pathways Beyond Ion Channels

Journal of Cardiovascular Translational Research volume 1, pages 155–165 (2008)Cite this article

Abstract

Diseases of the electrical conduction system that lead to irregularities in cardiac rhythm can have morbid and often lethal clinical outcomes. Linkage analysis has been the principal tool used to discover the genetic mutations responsible for Mendelian arrhythmic disease. Although the majority of arrhythmias can be accounted for by mutations in genes encoding ion channels, linkage analysis has also uncovered the role of other gene families such as those encoding members of the desmosome. With a list of candidates in mind, mutational analysis has helped confirm the suspicion that proteins found in caveolae or gap junctions also play a role in arrhythmogenesis. Atrial fibrillation and sudden cardiac death are relatively common arrhythmias that may be caused by multiple factors including common genetic variants. Genome-wide association studies are already revealing the important and poorly understood role of intergenic regions in atrial fibrillation. Despite the great advancements that have been made in our understanding of the genetics of these diseases, we are still far from able to routinely use genomic data to make clinical management decisions. There remain several hurdles in the study of genetics of arrhythmia, including the costs of genotyping, the need to find large affected families for linkage analysis, or to recruit large numbers of patients for genome-wide studies. Novel techniques that incorporate epigenetic information, such as known gene–gene interactions, biologic pathways, and experimental gene expression, will need to be developed to better interpret the large amount of genetic data that can now be generated. The study of arrhythmia genetics will continue to elucidate the pathophysiology of disease, help identify novel therapies, and ultimately allow us to deliver the individualized medical therapy that has long been anticipated.

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References

  1. International Human Genome Sequencing Consortium (2004). Finishing the euchromatic sequence of the human genome. Nature, 431(7011), 931–945.

    Article  CAS  Google Scholar 

  2. Priori, S. G., & Napolitano, C. (2006). Role of genetic analyses in cardiology: part I: mendelian diseases: cardiac channelopathies. Circulation, 113(8), 1130–1135.

    PubMed  Article  Google Scholar 

  3. Curran, M. E., Splawski, I., Timothy, K. W., Vincent, G. M., Green, E. D., & Keating, M. T. (1995). A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell, 80(5), 795–803.

    PubMed  Article  CAS  Google Scholar 

  4. Wang, Q., Shen, J., Splawski, I., et al. (1995). SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell, 80(5), 805–811.

    PubMed  Article  CAS  Google Scholar 

  5. Gudbjartsson, D. F., Arnar, D. O., Helgadottir, A., et al. (2007). Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature, 448(7151), 353–357.

    PubMed  Article  CAS  Google Scholar 

  6. Roeder, K., Devlin, B., & Wasserman, L. (2007). Improving power in genome-wide association studies: weights tip the scale. Genetic Epidemiology, 31(7), 741–747.

    PubMed  Article  Google Scholar 

  7. Karaoz, U., Murali, T. M., Letovsky, S., et al. (2004). Whole-genome annotation by using evidence integration in functional-linkage networks. Proceedings of the National Academy of Sciences of the United States of America, 101(9), 2888–2893.

    PubMed  Article  CAS  Google Scholar 

  8. Mendel, J. G. (1866). Experiments in plant hybridization. Abhandlungen, 4, 3–47.

    Google Scholar 

  9. Morgan, T. H. (1938). The theory of the gene. New Haven: Yale University Press.

    Google Scholar 

  10. Neher, E., & Sakmann, B. (1976). Single-channel currents recorded from membrane of denervated frog muscle fibres. Nature, 260(5554), 799–802.

    PubMed  Article  CAS  Google Scholar 

  11. Noda, M., Takahashi, H., Tanabe, T., et al. (1982). Primary structure of alpha-subunit precursor of Torpedo californica acetylcholine receptor deduced from cDNA sequence. Nature, 299(5886), 793–797.

    PubMed  Article  CAS  Google Scholar 

  12. Riordan, J. R., Rommens, J. M., Kerem, B., et al. (1989). Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science, 245(4922), 1066–1073.

    PubMed  Article  CAS  Google Scholar 

  13. Wang, Q., Curran, M. E., Splawski, I., et al. (1996). Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nature Genetics, 12(1), 17–23.

    PubMed  Article  Google Scholar 

  14. Duggal, P., Vesely, M. R., Wattanasirichaigoon, D., Villafane, J., Kaushik, V., & Beggs, A. H. (1998). Mutation of the gene for IsK associated with both Jervell and Lange–Nielsen and Romano–Ward forms of Long-QT syndrome. Circulation, 97(2), 142–146.

    PubMed  CAS  Google Scholar 

  15. Plaster, N. M., Tawil, R., Tristani-Firouzi, M., et al. (2001). Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen’s syndrome. Cell, 105(4), 511–519.

    PubMed  Article  CAS  Google Scholar 

  16. Mohler, P. J., Schott, J. J., Gramolini, A. O., et al. (2003). Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death. Nature, 421(6923), 634–639.

    PubMed  Article  CAS  Google Scholar 

  17. Abbott, G. W., Sesti, F., Splawski, I., et al. (1999). MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell, 97(2), 175–187.

    PubMed  Article  CAS  Google Scholar 

  18. Modell, S. M., & Lehmann, M. H. (2006). The long QT syndrome family of cardiac ion channelopathies: a HuGE review. Genetics in Medicine, 8(3), 143–155.

    PubMed  Article  CAS  Google Scholar 

  19. Brugada, P., & Brugada, J. (1992). Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report. Journal of the American College of Cardiology, 20(6), 1391–1396.

    PubMed  CAS  Article  Google Scholar 

  20. Chen, Q., Kirsch, G. E., Zhang, D., et al. (1998). Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature, 392(6673), 293–296.

    PubMed  Article  CAS  Google Scholar 

  21. Chen, Y. H., Xu, S. J., Bendahhou, S., et al. (2003). KCNQ1 gain-of-function mutation in familial atrial fibrillation. Science, 299(5604), 251–254.

    PubMed  Article  CAS  Google Scholar 

  22. Yang, Y., Xia, M., Jin, Q., et al. (2004). Identification of a KCNE2 gain-of-function mutation in patients with familial atrial fibrillation. American Journal of Human Genetics, 75(5), 899–905.

    PubMed  Article  CAS  Google Scholar 

  23. Bellocq, C., van Ginneken, A. C., Bezzina, C. R., et al. (2004). Mutation in the KCNQ1 gene leading to the short QT-interval syndrome. Circulation, 109(20), 2394–2397.

    PubMed  Article  Google Scholar 

  24. Antzelevitch, C., Pollevick, G. D., Cordeiro, J. M., et al. (2007). Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. Circulation, 115(4), 442–449.

    PubMed  Article  Google Scholar 

  25. Laitinen, P. J., Brown, K. M., Piippo, K., et al. (2001). Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia. Circulation, 103(4), 485–490.

    PubMed  CAS  Google Scholar 

  26. Brugada, R., Hong, K., Dumaine, R., et al. (2004). Sudden death associated with short-QT syndrome linked to mutations in HERG. Circulation, 109(1), 30–35.

    PubMed  Article  CAS  Google Scholar 

  27. Priori, S. G., Pandit, S. V., Rivolta, I., et al. (2005). A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene. Circulation Research, 96(7), 800–807.

    PubMed  Article  CAS  Google Scholar 

  28. Tiso, N., Stephan, D. A., Nava, A., et al. (2001). Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2). Human Molecular Genetics, 10(3), 189–194.

    PubMed  Article  CAS  Google Scholar 

  29. Hong, K., Bjerregaard, P., Gussak, I., & Brugada, R. (2005). Short QT syndrome and atrial fibrillation caused by mutation in KCNH2. Journal of Cardiovascular Electrophysiology, 16(4), 394–396.

    PubMed  Google Scholar 

  30. Milanesi, R., Baruscotti, M., Gnecchi-Ruscone, T., & DiFrancesco, D. (2006). Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel. New England Journal of Medicine, 354(2), 151–157.

    PubMed  Article  CAS  Google Scholar 

  31. McKoy, G., Protonotarios, N., Crosby, A., et al. (2000). Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease). Lancet, 355(9221), 2119–2124.

    PubMed  Article  CAS  Google Scholar 

  32. Rampazzo, A., Nava, A., Malacrida, S., et al. (2002). Mutation in human desmoplakin domain binding to plakoglobin causes a dominant form of arrhythmogenic right ventricular cardiomyopathy. American Journal of Human Genetics, 71(5), 1200–1206.

    PubMed  Article  CAS  Google Scholar 

  33. Alcalai, R., Metzger, S., Rosenheck, S., Meiner, V., & Chajek-Shaul, T. (2003). A recessive mutation in desmoplakin causes arrhythmogenic right ventricular dysplasia, skin disorder, and woolly hair. Journal of the American College of Cardiology, 42(2), 319–327.

    PubMed  Article  CAS  Google Scholar 

  34. Braunwald, E., Lambrew, C. T., Rockoff, S. D., Ross Jr., J., & Morrow, A. G. (1964). Idiopathic Hypertrophic Subaortic Stenosis. I. a Description of the Disease Based Upon an Analysis of 64 Patients. Circulation, 30(Suppl 4), 3–119.

    PubMed  Google Scholar 

  35. Adabag, A. S., Casey, S. A., Kuskowski, M. A., Zenovich, A. G., & Maron, B. J. (2005). Spectrum and prognostic significance of arrhythmias on ambulatory Holter electrocardiogram in hypertrophic cardiomyopathy. Journal of the American College of Cardiology, 45(5), 697–704.

    PubMed  Article  Google Scholar 

  36. Geisterfer-Lowrance, A. A., Kass, S., Tanigawa, G., et al. (1990). A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation. Cell, 62(5), 999–1006.

    PubMed  Article  CAS  Google Scholar 

  37. Poetter, K., Jiang, H., Hassanzadeh, S., et al. (1996). Mutations in either the essential or regulatory light chains of myosin are associated with a rare myopathy in human heart and skeletal muscle. Nature Genetics, 13(1), 63–69.

    PubMed  Article  CAS  Google Scholar 

  38. Watkins, H., Conner, D., Thierfelder, L., et al. (1995). Mutations in the cardiac myosin binding protein-C gene on chromosome 11 cause familial hypertrophic cardiomyopathy. Nature Genetics, 11(4), 434–437.

    PubMed  Article  CAS  Google Scholar 

  39. Thierfelder, L., Watkins, H., MacRae, C., et al. (1994). Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere. Cell, 77(5), 701–712.

    PubMed  Article  Google Scholar 

  40. Kimura, A., Harada, H., Park, J. E., et al. (1997). Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy. Nature Genetics, 16(4), 379–382.

    PubMed  Article  CAS  Google Scholar 

  41. Olson, T. M., Karst, M. L., Whitby, F. G., & Driscoll, D. J. (2002). Myosin light chain mutation causes autosomal recessive cardiomyopathy with mid-cavitary hypertrophy and restrictive physiology. Circulation, 105(20), 2337–2340.

    PubMed  Article  CAS  Google Scholar 

  42. Mogensen, J., Klausen, I. C., Pedersen, A. K., et al. (1999). Alpha-cardiac actin is a novel disease gene in familial hypertrophic cardiomyopathy. Journal of Clinical Investigation, 103(10), R39–R43.

    PubMed  Article  CAS  Google Scholar 

  43. Bos, J. M., Ommen, S. R., & Ackerman, M. J. (2007). Genetics of hypertrophic cardiomyopathy: One, two, or more diseases. Current Opinion in Cardiology, 22(3), 193–199.

    PubMed  Article  Google Scholar 

  44. Moss, A. J., Schwartz, P. J., Crampton, R. S., et al. (1991). The long QT syndrome. Prospective longitudinal study of 328 families. Circulation, 84(3), 1136–1144.

    PubMed  CAS  Google Scholar 

  45. Grossmann, K. S., Grund, C., Huelsken, J., et al. (2004). Requirement of plakophilin 2 for heart morphogenesis and cardiac junction formation. Journal of Cell Biology, 167(1), 149–160.

    PubMed  Article  CAS  Google Scholar 

  46. Gerull, B., Heuser, A., Wichter, T., et al. (2004). Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy. Nature Genetics, 36(11), 1162–1164.

    PubMed  Article  CAS  Google Scholar 

  47. Pilichou, K., Nava, A., Basso, C., et al. (2006). Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricular cardiomyopathy. Circulation, 113(9), 1171–1179.

    PubMed  Article  CAS  Google Scholar 

  48. Syrris, P., Ward, D., Evans, A., et al. (2006). Arrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in the desmosomal gene desmocollin-2. American Journal of Human Genetics, 79(5), 978–984.

    PubMed  Article  CAS  Google Scholar 

  49. Wang, D. W., Viswanathan, P. C., Balser, J. R., George Jr., A. L., & Benson, D. W. (2002). Clinical, genetic, and biophysical characterization of SCN5A mutations associated with atrioventricular conduction block. Circulation, 105(3), 341–346.

    PubMed  Article  CAS  Google Scholar 

  50. Vatta, M., Ackerman, M. J., Ye, B., et al. (2006). Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome. Circulation, 114(20), 2104–2112.

    PubMed  Article  CAS  Google Scholar 

  51. Xia, M., Jin, Q., Bendahhou, S., et al. (2005). A Kir2.1 gain-of-function mutation underlies familial atrial fibrillation. Biochemical and Biophysical Research Communications, 332(4), 1012–1019.

    PubMed  Article  CAS  Google Scholar 

  52. Olson, T. M., Alekseev, A. E., Liu, X. K., et al. (2006). Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation. Human Molecular Genetics, 15(14), 2185–2191.

    PubMed  Article  CAS  Google Scholar 

  53. Mohler, P. J., Le Scouarnec, S., Denjoy, I., et al. (2007). Defining the cellular phenotype of “ankyrin-B syndrome” variants: human ANK2 variants associated with clinical phenotypes display a spectrum of activities in cardiomyocytes. Circulation, 115(4), 432–441.

    PubMed  Article  Google Scholar 

  54. Olson, T. M., Alekseev, A. E., Moreau, C., et al. (2007). KATP channel mutation confers risk for vein of Marshall adrenergic atrial fibrillation. Nature Clinical Practice Cardiovascular Medicine, 4(2), 110–116.

    PubMed  Article  CAS  Google Scholar 

  55. Carniel, E., Taylor, M. R., Sinagra, G., et al. (2005). Alpha-myosin heavy chain: A sarcomeric gene associated with dilated and hypertrophic phenotypes of cardiomyopathy. Circulation, 112(1), 54–59.

    PubMed  Article  CAS  Google Scholar 

  56. Yang, Q., Khoury, M. J., Friedman, J., Little, J., & Flanders, W. D. (2005). How many genes underlie the occurrence of common complex diseases in the population. International Journal of Epidemiology, 34(5), 1129–1137.

    PubMed  Article  Google Scholar 

  57. Arnar, D. O., Thorvaldsson, S., Manolio, T. A., et al. (2006). Familial aggregation of atrial fibrillation in Iceland. European Heart Journal, 27(6), 708–712.

    PubMed  Article  Google Scholar 

  58. Yamashita, T., Hayami, N., Ajiki, K., et al. (1997). Is ACE gene polymorphism associated with lone atrial fibrillation. Japanese Heart Journal, 38(5), 637–641.

    PubMed  CAS  Google Scholar 

  59. Tsai, C. T., Lai, L. P., Lin, J. L., et al. (2004). Renin-angiotensin system gene polymorphisms and atrial fibrillation. Circulation, 109(13), 1640–1646.

    PubMed  Article  CAS  Google Scholar 

  60. Asselbergs, F. W., Moore, J. H., van den Berg, M. P., et al. (2006). A role for CETP TaqIB polymorphism in determining susceptibility to atrial fibrillation: a nested case control study. BMC Medical Genetics, 7, 39.

    PubMed  Article  CAS  Google Scholar 

  61. 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. Cardiovascular Research, 67(3), 520–528.

    PubMed  Article  CAS  Google Scholar 

  62. Zeng, Z., Tan, C., Teng, S., et al. (2007). The single nucleotide polymorphisms of I(Ks) potassium channel genes and their association with atrial fibrillation in a Chinese population. Cardiology, 108(2), 97–103.

    PubMed  Article  CAS  Google Scholar 

  63. Ravn, L. S., Hofman-Bang, J., Dixen, U., et al. (2005). Relation of 97T polymorphism in KCNE5 to risk of atrial fibrillation. American Journal of Cardiology, 96(3), 405–407.

    PubMed  Article  CAS  Google Scholar 

  64. Juang, J. M., Chern, Y. R., Tsai, C. T., et al. (2007). The association of human connexin 40 genetic polymorphisms with atrial fibrillation. International Journal of Cardiology, 116(1), 107–112.

    PubMed  Article  Google Scholar 

  65. Schreieck, J., Dostal, S., von Beckerath, N., et al. (2004). C825T polymorphism of the G-protein beta3 subunit gene and atrial fibrillation: association of the TT genotype with a reduced risk for atrial fibrillation. American Heart Journal, 148(3), 545–550.

    PubMed  Article  CAS  Google Scholar 

  66. Zheng, Z. J., Croft, J. B., Giles, W. H., & Mensah, G. A. (2001). Sudden cardiac death in the United States, 1989 to 1998. Circulation, 104(18), 2158–2163.

    PubMed  Article  CAS  Google Scholar 

  67. Sotoodehnia, N., Siscovick, D. S., Vatta, M., et al. (2006). Beta2-adrenergic receptor genetic variants and risk of sudden cardiac death. Circulation, 113(15), 1842–1848.

    PubMed  Article  CAS  Google Scholar 

  68. Burke, A., Creighton, W., Mont, E., et al. (2005). Role of SCN5A Y1102 polymorphism in sudden cardiac death in blacks. Circulation, 112(6), 798–802.

    PubMed  Article  CAS  Google Scholar 

  69. Fan, Y. M., Lehtimaki, T., Rontu, R., et al. (2007). The hepatic lipase gene C-480T polymorphism in the development of early coronary atherosclerosis: The Helsinki Sudden Death Study. European Journal of Clinical Investigation, 37(6), 472–477.

    PubMed  Article  CAS  Google Scholar 

  70. Hernesniemi, J. A., Karhunen, P. J., Rontu, R., et al. (2007). Interleukin-18 promoter polymorphism associates with the occurrence of sudden cardiac death among Caucasian males: The Helsinki Sudden Death Study. Atherosclerosis, 196, 643–649.

    Google Scholar 

  71. Mikkelsson, J., Perola, M., Penttila, A., & Karhunen, P. J. (2001). Platelet glycoprotein Ibalpha HPA-2 Met/VNTR B haplotype as a genetic predictor of myocardial infarction and sudden cardiac death. Circulation, 104(8), 876–880.

    PubMed  Article  CAS  Google Scholar 

  72. Arking, D. E., Pfeufer, A., Post, W., et al. (2006). A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization. Nature Genetics, 38(6), 644–651.

    PubMed  Article  CAS  Google Scholar 

  73. Newton-Cheh, C., Guo, C. Y., Larson, M. G., et al. (2007). Common genetic variation in KCNH2 is associated with QT interval duration: the Framingham Heart Study. Circulation, 116(10), 1128–1136.

    PubMed  Article  CAS  Google Scholar 

  74. The International HapMap Project. (2003). Nature, 426(6968), 789–796.

    Google Scholar 

  75. Wang, W. Y., Barratt, B. J., Clayton, D. G., & Todd, J. A. (2005). Genome-wide association studies: theoretical and practical concerns. Nature Reviews. Genetics, 6(2), 109–118.

    PubMed  Article  CAS  Google Scholar 

  76. The Wellcome Trust Case Control Consortium (2007). Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature, 447(7145), 661–678.

    Article  CAS  Google Scholar 

  77. Yang, Z., Camp, N. J., Sun, H., et al. (2006). A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science, 314(5801), 992–993.

    PubMed  Article  CAS  Google Scholar 

  78. Saxena, R., Voight, B. F., Lyssenko, V., et al. (2007). Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science, 316(5829), 1331–1336.

    PubMed  Article  CAS  Google Scholar 

  79. Newton-Cheh, C., Guo, C. Y., Wang, T. J., O’Donnell, C. J., Levy, D., & Larson, M. G. (2007). Genome-wide association study of electrocardiographic and heart rate variability traits: The Framingham Heart Study. BMC Medical Genetics, 8(Suppl 1), S7.

    PubMed  Article  CAS  Google Scholar 

  80. Morgan, T. M., Krumholz, H. M., Lifton, R. P., & Spertus, J. A. (2007). Nonvalidation of reported genetic risk factors for acute coronary syndrome in a large-scale replication study. JAMA, 297(14), 1551–1561.

    PubMed  Article  CAS  Google Scholar 

  81. Ioannidis, J. P. (2007). Non-replication and inconsistency in the genome-wide association setting. Human Heredity, 64(4), 203–213.

    PubMed  Article  CAS  Google Scholar 

  82. Serre, D., Montpetit, A., Pare, G., et al. (2008). Correction of population stratification in large multi-ethnic association studies. PLoS ONE, 3(1), e1382.

    PubMed  Article  Google Scholar 

  83. Moss, A. J., Zareba, W., Hall, W. J., et al. (2000). Effectiveness and limitations of beta-blocker therapy in congenital long-QT syndrome. Circulation, 101(6), 616–623.

    PubMed  CAS  Google Scholar 

  84. Phillips, K. A., Ackerman, M. J., Sakowski, J., & Berul, C. I. (2005). Cost-effectiveness analysis of genetic testing for familial long QT syndrome in symptomatic index cases. Heart Rhythm, 2(12), 1294–300.

    PubMed  Article  Google Scholar 

  85. Siddoway, L. A., Thompson, K. A., McAllister, C. B., et al. (1987). Polymorphism of propafenone metabolism and disposition in man: clinical and pharmacokinetic consequences. Circulation, 75(4), 785–791.

    PubMed  CAS  Google Scholar 

  86. Okumura, K., Kita, T., Chikazawa, S., Komada, F., Iwakawa, S., & Tanigawara, Y. (1997). Genotyping of N-acetylation polymorphism and correlation with procainamide metabolism. Clinical Pharmacology and Therapeutics, 61(5), 509–517.

    PubMed  CAS  Article  Google Scholar 

  87. Shuraih, M., Ai, T., Vatta, M., et al. (2007). A common SCN5A variant alters the responsiveness of human sodium channels to class I antiarrhythmic agents. Journal of Cardiovascular Electrophysiology, 18(4), 434–440.

    PubMed  Article  Google Scholar 

  88. Sun, Z., Milos, P. M., Thompson, J. F., et al. (2004). Role of a KCNH2 polymorphism (R1047 L) in dofetilide-induced Torsades de Pointes. Journal of Molecular and Cellular Cardiology, 37(5), 1031–1039.

    PubMed  Article  CAS  Google Scholar 

  89. Marques-Bonet, T., Lao, O., Goertsches, R., Comabella, M., Montalban, X., & Navarro, A. (2005). Association Cluster Detector: a tool for heuristic detection of significance clusters in whole-genome scans. Bioinformatics, 21(Suppl 2), ii180–ii181.

    PubMed  Article  CAS  Google Scholar 

  90. Tomida, S., Hanai, T., Koma, N., Suzuki, Y., Kobayashi, T., & Honda, H. (2002). Artificial neural network predictive model for allergic disease using single nucleotide polymorphisms data. Journal of Bioscience and Bioengineering, 93(5), 470–478.

    PubMed  CAS  Google Scholar 

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  1. Division of Cardiovascular Medicine, Stanford University, 300 Pasteur Drive, Falk CVRC MC, 5406, Stanford, CA, 94305, USA

    Marco V. Perez, Matthew Wheeler, Michael Ho, Aleksandra Pavlovic, Paul Wang & Euan A. Ashley

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Perez, M.V., Wheeler, M., Ho, M. et al. Genetics of Arrhythmia: Disease Pathways Beyond Ion Channels. J. of Cardiovasc. Trans. Res. 1, 155–165 (2008). https://doi.org/10.1007/s12265-008-9030-4

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Keywords

  • Arrhythmia
  • Genetics
  • LQTS
  • Atrial Fibrillation
  • Review
  • Electrophysiology