title: Genetic Modifiers for the Long-QT Syndrome: How Important Is the Role of Variants in the 3' Untranslated Region of KCNQ1?
abstract: BACKGROUND
  Long-QT syndrome is an inherited cardiac channelopathy characterized by delayed repolarization, risk of life-threatening arrhythmia, and significant clinical variability even within families. Three single-nucleotide polymorphisms (SNPs) in the 3' untranslated region of KCNQ1 were recently suggested to be associated with suppressed gene expression and hence decreased disease severity when located on the same haplotype with a disease-causing KCNQ1 mutation. We sought to replicate this finding in a larger and a genetically more homogeneous population of KCNQ1 mutation carriers.
  
  
  RESULTS
  The 3 SNPs (rs2519184, rs8234, and rs10798) were genotyped in a total of 747 KCNQ1 mutation carriers with A341V, G589D, or IVS7-2A>G mutation. The SNP haplotypes were assigned based on family trees. The SNP allele frequencies and clinical severity differed between the 3 mutation groups. The different SNP haplotypes were neither associated with heart rate-corrected QT interval duration (QTc) nor cardiac events in any of the 3 mutation groups. When the mutation groups were combined, the derived SNP haplotype of rs8234 and rs10798 located on the same haplotype with the mutation was associated with a shorter QTc interval (P<0.05) and a reduced occurrence of cardiac events (P<0.01), consistent with the previous finding. However, when the population-specific mutation was controlled for, both associations were no longer evident.
  
  
  CONCLUSIONS
  3' Untranslated region SNPs are not acting as genetic modifiers in a large group of LQT1 patients. The confounding effect of merging a genetically and clinically heterogeneous group of patients needs to be taken into account when studying disease modifiers.
authors.affiliation: From the Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan (L.C., C.S., P.J.S.); Department of Molecular Medicine (L.C.) and Department of Public Health (M.C.M., C.M.), Unit of Biostatistics and Clinical Epidemiology, University of Pavia, Pavia; Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital IRCCS Istituto Auxologico Italiano, Milan, Italy (L.C., G.P.); Department of Medicine, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland (A.M.L., K.K.); Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany (E.M., P.L., T.M.); Department of Medicine and Surgery University of Milano-Bicocca, Milan, Italy (G.P.); Department of Internal Medicine, University of Stellenbosch, South Africa (M.H., A.G., P.A.B.); Institute of Human Genetics, Technische Universität München (T.M.); DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (T.M.); and Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland (H.S.). l.crotti@auxologico.it.
authors.forename: Lia
authors.initials: L
authors.lastname: Crotti
authors.affiliation: From the Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan (L.C., C.S., P.J.S.); Department of Molecular Medicine (L.C.) and Department of Public Health (M.C.M., C.M.), Unit of Biostatistics and Clinical Epidemiology, University of Pavia, Pavia; Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital IRCCS Istituto Auxologico Italiano, Milan, Italy (L.C., G.P.); Department of Medicine, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland (A.M.L., K.K.); Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany (E.M., P.L., T.M.); Department of Medicine and Surgery University of Milano-Bicocca, Milan, Italy (G.P.); Department of Internal Medicine, University of Stellenbosch, South Africa (M.H., A.G., P.A.B.); Institute of Human Genetics, Technische Universität München (T.M.); DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (T.M.); and Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland (H.S.).
authors.forename: Annukka M
authors.initials: AM
authors.lastname: Lahtinen
authors.affiliation: From the Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan (L.C., C.S., P.J.S.); Department of Molecular Medicine (L.C.) and Department of Public Health (M.C.M., C.M.), Unit of Biostatistics and Clinical Epidemiology, University of Pavia, Pavia; Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital IRCCS Istituto Auxologico Italiano, Milan, Italy (L.C., G.P.); Department of Medicine, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland (A.M.L., K.K.); Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany (E.M., P.L., T.M.); Department of Medicine and Surgery University of Milano-Bicocca, Milan, Italy (G.P.); Department of Internal Medicine, University of Stellenbosch, South Africa (M.H., A.G., P.A.B.); Institute of Human Genetics, Technische Universität München (T.M.); DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (T.M.); and Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland (H.S.).
authors.forename: Carla
authors.initials: C
authors.lastname: Spazzolini
authors.affiliation: From the Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan (L.C., C.S., P.J.S.); Department of Molecular Medicine (L.C.) and Department of Public Health (M.C.M., C.M.), Unit of Biostatistics and Clinical Epidemiology, University of Pavia, Pavia; Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital IRCCS Istituto Auxologico Italiano, Milan, Italy (L.C., G.P.); Department of Medicine, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland (A.M.L., K.K.); Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany (E.M., P.L., T.M.); Department of Medicine and Surgery University of Milano-Bicocca, Milan, Italy (G.P.); Department of Internal Medicine, University of Stellenbosch, South Africa (M.H., A.G., P.A.B.); Institute of Human Genetics, Technische Universität München (T.M.); DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (T.M.); and Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland (H.S.).
authors.forename: Elisa
authors.initials: E
authors.lastname: Mastantuono
authors.affiliation: From the Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan (L.C., C.S., P.J.S.); Department of Molecular Medicine (L.C.) and Department of Public Health (M.C.M., C.M.), Unit of Biostatistics and Clinical Epidemiology, University of Pavia, Pavia; Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital IRCCS Istituto Auxologico Italiano, Milan, Italy (L.C., G.P.); Department of Medicine, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland (A.M.L., K.K.); Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany (E.M., P.L., T.M.); Department of Medicine and Surgery University of Milano-Bicocca, Milan, Italy (G.P.); Department of Internal Medicine, University of Stellenbosch, South Africa (M.H., A.G., P.A.B.); Institute of Human Genetics, Technische Universität München (T.M.); DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (T.M.); and Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland (H.S.).
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Monti
authors.affiliation: From the Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan (L.C., C.S., P.J.S.); Department of Molecular Medicine (L.C.) and Department of Public Health (M.C.M., C.M.), Unit of Biostatistics and Clinical Epidemiology, University of Pavia, Pavia; Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital IRCCS Istituto Auxologico Italiano, Milan, Italy (L.C., G.P.); Department of Medicine, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland (A.M.L., K.K.); Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany (E.M., P.L., T.M.); Department of Medicine and Surgery University of Milano-Bicocca, Milan, Italy (G.P.); Department of Internal Medicine, University of Stellenbosch, South Africa (M.H., A.G., P.A.B.); Institute of Human Genetics, Technische Universität München (T.M.); DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (T.M.); and Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland (H.S.).
authors.forename: Caterina
authors.initials: C
authors.lastname: Morassutto
authors.affiliation: From the Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan (L.C., C.S., P.J.S.); Department of Molecular Medicine (L.C.) and Department of Public Health (M.C.M., C.M.), Unit of Biostatistics and Clinical Epidemiology, University of Pavia, Pavia; Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital IRCCS Istituto Auxologico Italiano, Milan, Italy (L.C., G.P.); Department of Medicine, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland (A.M.L., K.K.); Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany (E.M., P.L., T.M.); Department of Medicine and Surgery University of Milano-Bicocca, Milan, Italy (G.P.); Department of Internal Medicine, University of Stellenbosch, South Africa (M.H., A.G., P.A.B.); Institute of Human Genetics, Technische Universität München (T.M.); DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (T.M.); and Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland (H.S.).
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Parati
authors.affiliation: From the Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan (L.C., C.S., P.J.S.); Department of Molecular Medicine (L.C.) and Department of Public Health (M.C.M., C.M.), Unit of Biostatistics and Clinical Epidemiology, University of Pavia, Pavia; Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital IRCCS Istituto Auxologico Italiano, Milan, Italy (L.C., G.P.); Department of Medicine, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland (A.M.L., K.K.); Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany (E.M., P.L., T.M.); Department of Medicine and Surgery University of Milano-Bicocca, Milan, Italy (G.P.); Department of Internal Medicine, University of Stellenbosch, South Africa (M.H., A.G., P.A.B.); Institute of Human Genetics, Technische Universität München (T.M.); DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (T.M.); and Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland (H.S.).
authors.forename: Marshall
authors.initials: M
authors.lastname: Heradien
authors.affiliation: From the Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan (L.C., C.S., P.J.S.); Department of Molecular Medicine (L.C.) and Department of Public Health (M.C.M., C.M.), Unit of Biostatistics and Clinical Epidemiology, University of Pavia, Pavia; Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital IRCCS Istituto Auxologico Italiano, Milan, Italy (L.C., G.P.); Department of Medicine, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland (A.M.L., K.K.); Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany (E.M., P.L., T.M.); Department of Medicine and Surgery University of Milano-Bicocca, Milan, Italy (G.P.); Department of Internal Medicine, University of Stellenbosch, South Africa (M.H., A.G., P.A.B.); Institute of Human Genetics, Technische Universität München (T.M.); DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (T.M.); and Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland (H.S.).
authors.forename: Althea
authors.initials: A
authors.lastname: Goosen
authors.affiliation: From the Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan (L.C., C.S., P.J.S.); Department of Molecular Medicine (L.C.) and Department of Public Health (M.C.M., C.M.), Unit of Biostatistics and Clinical Epidemiology, University of Pavia, Pavia; Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital IRCCS Istituto Auxologico Italiano, Milan, Italy (L.C., G.P.); Department of Medicine, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland (A.M.L., K.K.); Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany (E.M., P.L., T.M.); Department of Medicine and Surgery University of Milano-Bicocca, Milan, Italy (G.P.); Department of Internal Medicine, University of Stellenbosch, South Africa (M.H., A.G., P.A.B.); Institute of Human Genetics, Technische Universität München (T.M.); DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (T.M.); and Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland (H.S.).
authors.forename: Peter
authors.initials: P
authors.lastname: Lichtner
authors.affiliation: From the Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan (L.C., C.S., P.J.S.); Department of Molecular Medicine (L.C.) and Department of Public Health (M.C.M., C.M.), Unit of Biostatistics and Clinical Epidemiology, University of Pavia, Pavia; Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital IRCCS Istituto Auxologico Italiano, Milan, Italy (L.C., G.P.); Department of Medicine, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland (A.M.L., K.K.); Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany (E.M., P.L., T.M.); Department of Medicine and Surgery University of Milano-Bicocca, Milan, Italy (G.P.); Department of Internal Medicine, University of Stellenbosch, South Africa (M.H., A.G., P.A.B.); Institute of Human Genetics, Technische Universität München (T.M.); DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (T.M.); and Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland (H.S.).
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.affiliation: From the Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan (L.C., C.S., P.J.S.); Department of Molecular Medicine (L.C.) and Department of Public Health (M.C.M., C.M.), Unit of Biostatistics and Clinical Epidemiology, University of Pavia, Pavia; Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital IRCCS Istituto Auxologico Italiano, Milan, Italy (L.C., G.P.); Department of Medicine, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland (A.M.L., K.K.); Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany (E.M., P.L., T.M.); Department of Medicine and Surgery University of Milano-Bicocca, Milan, Italy (G.P.); Department of Internal Medicine, University of Stellenbosch, South Africa (M.H., A.G., P.A.B.); Institute of Human Genetics, Technische Universität München (T.M.); DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (T.M.); and Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland (H.S.).
authors.forename: Paul A
authors.initials: PA
authors.lastname: Brink
authors.affiliation: From the Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan (L.C., C.S., P.J.S.); Department of Molecular Medicine (L.C.) and Department of Public Health (M.C.M., C.M.), Unit of Biostatistics and Clinical Epidemiology, University of Pavia, Pavia; Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital IRCCS Istituto Auxologico Italiano, Milan, Italy (L.C., G.P.); Department of Medicine, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland (A.M.L., K.K.); Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany (E.M., P.L., T.M.); Department of Medicine and Surgery University of Milano-Bicocca, Milan, Italy (G.P.); Department of Internal Medicine, University of Stellenbosch, South Africa (M.H., A.G., P.A.B.); Institute of Human Genetics, Technische Universität München (T.M.); DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (T.M.); and Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland (H.S.).
authors.forename: Kimmo
authors.initials: K
authors.lastname: Kontula
authors.affiliation: From the Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan (L.C., C.S., P.J.S.); Department of Molecular Medicine (L.C.) and Department of Public Health (M.C.M., C.M.), Unit of Biostatistics and Clinical Epidemiology, University of Pavia, Pavia; Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital IRCCS Istituto Auxologico Italiano, Milan, Italy (L.C., G.P.); Department of Medicine, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland (A.M.L., K.K.); Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany (E.M., P.L., T.M.); Department of Medicine and Surgery University of Milano-Bicocca, Milan, Italy (G.P.); Department of Internal Medicine, University of Stellenbosch, South Africa (M.H., A.G., P.A.B.); Institute of Human Genetics, Technische Universität München (T.M.); DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (T.M.); and Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland (H.S.).
authors.forename: Heikki
authors.initials: H
authors.lastname: Swan
authors.affiliation: From the Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan (L.C., C.S., P.J.S.); Department of Molecular Medicine (L.C.) and Department of Public Health (M.C.M., C.M.), Unit of Biostatistics and Clinical Epidemiology, University of Pavia, Pavia; Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital IRCCS Istituto Auxologico Italiano, Milan, Italy (L.C., G.P.); Department of Medicine, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland (A.M.L., K.K.); Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany (E.M., P.L., T.M.); Department of Medicine and Surgery University of Milano-Bicocca, Milan, Italy (G.P.); Department of Internal Medicine, University of Stellenbosch, South Africa (M.H., A.G., P.A.B.); Institute of Human Genetics, Technische Universität München (T.M.); DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (T.M.); and Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland (H.S.).
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Schwartz
mesh_terms: D020413:3' Untranslated Regions; D005060:Europe; D005260:Female; D005787:Gene Frequency; D060045:Genes, Modifier; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D040941:Heredity; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D029597:Romano-Ward Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D012720:Severity of Illness Index; D013019:South Africa
chemical_list: D020413:3' Untranslated Regions; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human
keywords: KCNQ1 potassium channel; arrhythmias; genes, modifier; long-QT syndrome; untranslated region