Ethnic differences in cardiac potassium channel variants: implications for genetic susceptibility to sudden cardiac death and genetic testing for congenital long QT syndrome.

OBJECTIVE To determine the spectrum, frequency, and ethnic-specificity of channel variants in the potassium channel genes implicated in congenital long QT syndrome (LQTS) among healthy subjects. SUBJECTS AND METHODS Genomic DNA from 744 apparently healthy individuals-305 black, 187 white, 134 Asian, and 118 Hispanic--was subject to a comprehensive mutational analysis of the 4 LQTS-causing potassium channel genes: KCNQ1 (LQT1), KCNH2 (LQT2), KCNE1 (LQT5), and KCNE2 (LQT6). RESULTS Overall, 49 distinct amino acid-altering variants (36 novel) were identified: KCNQ1 (n = 16), KCNH2 (n = 25),KCNE1 (n = 5), and KCNE2 (n = 3). More than half of these variants (26/49) were found exclusively in black subjects. The known K897T-HERG and the G38S-min K common polymorphisms were identified in all 4 ethnic groups. Excluding these 2 common polymorphisms, 25% of black subjects had at least 1 nonsynonymous potassium channel variant compared with 14% of white subjects (P < .01). CONCLUSIONS To our knowledge, this study represents the first comprehensive determination of the frequency and spectrum of cardiac channel variants found among healthy subjects from 4 major ethnic groups. Defining the population burden of genetic variants in these critical cardiac ion channels is crucial for proper interpretation of genetic test results of individuals at risk for LQTS. This compendium provides a resource for epidemiological and functional investigation of variant effects on the repolarization properties of cardiac tissues, including susceptibility to lethal cardiac arrhythmias.

[1]  M. Ackerman,et al.  Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome , 2002 .

[2]  D. Roden,et al.  The genetic basis of variability in drug responses , 2002, Nature Reviews Drug Discovery.

[3]  Bernd Wollnik,et al.  The antihistamine fexofenadine does not affect IKr currents in a case report of drug‐induced cardiac arrhythmia , 2002, British journal of pharmacology.

[4]  J J Heger,et al.  Sudden cardiac death. , 1998, Circulation.

[5]  M. Keating,et al.  MiRP1 Forms IKr Potassium Channels with HERG and Is Associated with Cardiac Arrhythmia , 1999, Cell.

[6]  S. Antonarakis.  Recommendations for a nomenclature system for human gene mutations , 1998 .

[7]  M. Keating,et al.  Genomic structure of three long QT syndrome genes: KVLQT1, HERG, and KCNE1. , 1998, Genomics.

[8]  M J Ackerman,et al.  The long QT syndrome: ion channel diseases of the heart. , 1998, Mayo Clinic proceedings.

[9]  E. Green,et al.  A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome , 1995, Cell.

[10]  Steven L. Cohen,et al.  DEPARTMENT OF PHYSIOLOGY: 2016/2017 LT/LE ORGANIZATION CHART , 2016 .

[11]  G. Breithardt,et al.  A novel long-QT 5 gene mutation in the C-terminus (V109I) is associated with a mild phenotype , 2001, Journal of Molecular Medicine.

[12]  A J Moss,et al.  Spectrum of Mutations in Long-QT Syndrome Genes: KVLQT1, HERG, SCN5A, KCNE1, and KCNE2 , 2000, Circulation.

[13]  M. Alderman,et al.  The association between birthplace and mortality from cardiovascular causes among black and white residents of New York City. , 1996, The New England journal of medicine.

[14]  H. Smeets,et al.  Novel KCNQ1 and HERG missense mutations in Dutch long‐QT families , 1999, Human mutation.

[15]  R. Elston,et al.  Sudden cardiac death, genes, and arrhythmogenesis: consideration of new population and mechanistic approaches from a National Heart, Lung, and Blood Institute workshop, Part II. , 2001, Circulation.

[16]  A. George,et al.  Molecular mechanism for an inherited cardiac arrhythmia , 1995, Nature.

[17]  M. Ackerman,et al.  The long QT syndrome. , 1998, Pediatrics in review.

[18]  M. Sanguinetti,et al.  Fast inactivation causes rectification of the IKr channel , 1996, The Journal of general physiology.

[19]  R. Cooper,et al.  Health and the social status of blacks in the United States. , 1993, Annals of epidemiology.

[20]  D. Roden.  Acquired Long QT Syndromes and the Risk of Proarrhythmia , 2000, Journal of cardiovascular electrophysiology.

[21]  F. Cappuccio,et al.  Variant of SCN5A Sodium Channel Implicated in Risk of Cardiac Arrhythmia , 2002, Science.

[22]  H. Huikuri,et al.  Sudden death due to cardiac arrhythmias. , 2001, The New England journal of medicine.

[23]  C. January,et al.  Novel mechanism associated with an inherited cardiac arrhythmia: defective protein trafficking by the mutant HERG (G601S) potassium channel. , 1999, Circulation.

[24]  G. Landes,et al.  Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias , 1996, Nature Genetics.

[25]  A. Paulussen,et al.  A Novel Mutation (T65P) in the PAS Domain of the Human Potassium Channel HERG Results in the Long QT Syndrome by Trafficking Deficiency* , 2002, The Journal of Biological Chemistry.

[26]  Arthur J Moss,et al.  SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome , 1995, Cell.

[27]  J. Towbin,et al.  Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome. , 2001, JAMA.

[28]  H. Huikuri,et al.  Association between HERG K897T polymorphism and QT interval in middle-aged Finnish women. , 2002, Journal of the American College of Cardiology.

[29]  Junko Kurokawa,et al.  Requirement of a Macromolecular Signaling Complex for β Adrenergic Receptor Modulation of the KCNQ1-KCNE1 Potassium Channel , 2002, Science.

[30]  A. Gramolini,et al.  Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death , 2003, Nature.

[31]  A. Tajik,et al.  Prevalence and age-dependence of malignant mutations in the beta-myosin heavy chain and troponin T genes in hypertrophic cardiomyopathy: a comprehensive outpatient perspective. , 2002, Journal of the American College of Cardiology.

[32]  P. C. Viswanathan,et al.  Allelic Variants in Long-QT Disease Genes in Patients With Drug-Associated Torsades de Pointes , 2002, Circulation.

[33]  M. Sanguinetti,et al.  Molecular and Cellular Mechanisms of Cardiac Arrhythmias , 2001, Cell.

[34]  M. Horie,et al.  Evidence for a Single Nucleotide Polymorphism in the KCNQ1 Potassium Channel that Underlies Susceptibility to Life‐Threatening Arrhythmias , 2001, Journal of cardiovascular electrophysiology.

[35]  R. Gillum,et al.  Sudden coronary death in the United States: 1980-1985. , 1989, Circulation.

[36]  M. Sanguinetti,et al.  Coassembly of KVLQT1 and minK (IsK) proteins to form cardiac IKS potassium channel , 1996, Nature.

[37]  P. C. Viswanathan,et al.  Novel characteristics of a misprocessed mutant HERG channel linked to hereditary long QT syndrome. , 2000, American journal of physiology. Heart and circulatory physiology.

[38]  D. Clapham,et al.  Ion channels--basic science and clinical disease. , 1997, The New England journal of medicine.

[39]  D. Roden,et al.  Inherited Long QT Syndromes: , 1999, Journal of cardiovascular electrophysiology.

[40]  D. Roden.  Pharmacogenetics and drug-induced arrhythmias. , 2001, Cardiovascular research.

[41]  R. Kass,et al.  Requirement of subunit expression for cAMP-mediated regulation of a heart potassium channel , 2003, Proceedings of the National Academy of Sciences of the United States of America.