title: AKAP9 is a genetic modifier of congenital long-QT syndrome type 1.
abstract: BACKGROUND
  Long-QT syndrome (LQTS), a cardiac arrhythmia disorder with variable phenotype, often results in devastating outcomes, including sudden cardiac death. Variable expression, independently from the primary disease-causing mutation, can partly be explained by genetic modifiers. This study investigates variants in a known LQTS-causative gene, AKAP9, for potential LQTS-type 1-modifying effects.
  
  
  RESULTS
  Members of a South African LQTS-type 1 founder population (181 noncarriers and 168 mutation carriers) carrying the identical-by-descent KCNQ1 p.Ala341Val (A341V) mutation were evaluated for modifying effects of AKAP9 variants on heart rate-corrected QT interval (QTc), cardiac events, and disease severity. Tag single nucleotide polymorphisms in AKAP9 rs11772585, rs7808587, rs2282972, and rs2961024 (order, 5'-3'positive strand) were genotyped. Associations between phenotypic traits and alleles, genotypes, and haplotypes were statistically assessed, adjusting for the degree of relatedness and confounding variables. The rs2961024 GG genotype, always represented by CGCG haplotype homozygotes, revealed an age-dependent heart rate-corrected QT interval increase (1% per additional 10 years) irrespective of A341V mutation status (P=0.006). The rs11772585 T allele, found uniquely in the TACT haplotype, more than doubled (218%) the risk of cardiac events (P=0.002) in the presence of A341V; additionally, it increased disease severity (P=0.025). The rs7808587 GG genotype was associated with a 74% increase in cardiac event risk (P=0.046), whereas the rs2282972 T allele, predominantly represented by the CATT haplotype, decreased risk by 53% (P=0.001).
  
  
  CONCLUSIONS
  AKAP9 has been identified as an LQTS-type 1-modifying gene. Variants investigated altered heart rate-corrected QT interval irrespective of mutation status, as well as cardiac event risk, and disease severity, in mutation carriers.
authors.affiliation: From the Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Medical Research Council (MRC) Centre for Molecular and Cellular Biology, (C.P.d.V., L.v.d.M., J.C.M.-S., V.A.C.), and Department of Internal Medicine (A.G., P.A.B.), Stellenbosch University, Stellenbosch, South Africa; Department of Statistics, University of Western Cape, Bellville, South Africa (L.v.d.M.); IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy (L.C., P.J.S.); Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C.); Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany (L.C.); and Departments of Medicine and Pharmacology, and Institute for Integrative Genomics, Vanderbilt University, Nashville, TN (A.L.G.).
authors.forename: Carin P
authors.initials: CP
authors.lastname: de Villiers
authors.affiliation: From the Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Medical Research Council (MRC) Centre for Molecular and Cellular Biology, (C.P.d.V., L.v.d.M., J.C.M.-S., V.A.C.), and Department of Internal Medicine (A.G., P.A.B.), Stellenbosch University, Stellenbosch, South Africa; Department of Statistics, University of Western Cape, Bellville, South Africa (L.v.d.M.); IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy (L.C., P.J.S.); Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C.); Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany (L.C.); and Departments of Medicine and Pharmacology, and Institute for Integrative Genomics, Vanderbilt University, Nashville, TN (A.L.G.).
authors.forename: Lize
authors.initials: L
authors.lastname: van der Merwe
authors.affiliation: From the Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Medical Research Council (MRC) Centre for Molecular and Cellular Biology, (C.P.d.V., L.v.d.M., J.C.M.-S., V.A.C.), and Department of Internal Medicine (A.G., P.A.B.), Stellenbosch University, Stellenbosch, South Africa; Department of Statistics, University of Western Cape, Bellville, South Africa (L.v.d.M.); IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy (L.C., P.J.S.); Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C.); Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany (L.C.); and Departments of Medicine and Pharmacology, and Institute for Integrative Genomics, Vanderbilt University, Nashville, TN (A.L.G.).
authors.forename: Lia
authors.initials: L
authors.lastname: Crotti
authors.affiliation: From the Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Medical Research Council (MRC) Centre for Molecular and Cellular Biology, (C.P.d.V., L.v.d.M., J.C.M.-S., V.A.C.), and Department of Internal Medicine (A.G., P.A.B.), Stellenbosch University, Stellenbosch, South Africa; Department of Statistics, University of Western Cape, Bellville, South Africa (L.v.d.M.); IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy (L.C., P.J.S.); Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C.); Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany (L.C.); and Departments of Medicine and Pharmacology, and Institute for Integrative Genomics, Vanderbilt University, Nashville, TN (A.L.G.).
authors.forename: Althea
authors.initials: A
authors.lastname: Goosen
authors.affiliation: From the Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Medical Research Council (MRC) Centre for Molecular and Cellular Biology, (C.P.d.V., L.v.d.M., J.C.M.-S., V.A.C.), and Department of Internal Medicine (A.G., P.A.B.), Stellenbosch University, Stellenbosch, South Africa; Department of Statistics, University of Western Cape, Bellville, South Africa (L.v.d.M.); IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy (L.C., P.J.S.); Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C.); Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany (L.C.); and Departments of Medicine and Pharmacology, and Institute for Integrative Genomics, Vanderbilt University, Nashville, TN (A.L.G.).
authors.forename: Alfred L
authors.initials: AL
authors.lastname: George
authors.affiliation: From the Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Medical Research Council (MRC) Centre for Molecular and Cellular Biology, (C.P.d.V., L.v.d.M., J.C.M.-S., V.A.C.), and Department of Internal Medicine (A.G., P.A.B.), Stellenbosch University, Stellenbosch, South Africa; Department of Statistics, University of Western Cape, Bellville, South Africa (L.v.d.M.); IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy (L.C., P.J.S.); Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C.); Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany (L.C.); and Departments of Medicine and Pharmacology, and Institute for Integrative Genomics, Vanderbilt University, Nashville, TN (A.L.G.).
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Schwartz
authors.affiliation: From the Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Medical Research Council (MRC) Centre for Molecular and Cellular Biology, (C.P.d.V., L.v.d.M., J.C.M.-S., V.A.C.), and Department of Internal Medicine (A.G., P.A.B.), Stellenbosch University, Stellenbosch, South Africa; Department of Statistics, University of Western Cape, Bellville, South Africa (L.v.d.M.); IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy (L.C., P.J.S.); Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C.); Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany (L.C.); and Departments of Medicine and Pharmacology, and Institute for Integrative Genomics, Vanderbilt University, Nashville, TN (A.L.G.).
authors.forename: Paul A
authors.initials: PA
authors.lastname: Brink
authors.affiliation: From the Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Medical Research Council (MRC) Centre for Molecular and Cellular Biology, (C.P.d.V., L.v.d.M., J.C.M.-S., V.A.C.), and Department of Internal Medicine (A.G., P.A.B.), Stellenbosch University, Stellenbosch, South Africa; Department of Statistics, University of Western Cape, Bellville, South Africa (L.v.d.M.); IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy (L.C., P.J.S.); Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C.); Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany (L.C.); and Departments of Medicine and Pharmacology, and Institute for Integrative Genomics, Vanderbilt University, Nashville, TN (A.L.G.).
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Moolman-Smook
authors.affiliation: From the Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Medical Research Council (MRC) Centre for Molecular and Cellular Biology, (C.P.d.V., L.v.d.M., J.C.M.-S., V.A.C.), and Department of Internal Medicine (A.G., P.A.B.), Stellenbosch University, Stellenbosch, South Africa; Department of Statistics, University of Western Cape, Bellville, South Africa (L.v.d.M.); IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy (L.C., P.J.S.); Department of Molecular Medicine, University of Pavia, Pavia, Italy (L.C.); Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany (L.C.); and Departments of Medicine and Pharmacology, and Institute for Integrative Genomics, Vanderbilt University, Nashville, TN (A.L.G.).
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Corfield
mesh_terms: D054758:A Kinase Anchor Proteins / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000483:Alleles; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D018703:Founder Effect; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D007962:Leukocytes / Q000166:cytology; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D009154:Mutation; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D029597:Romano-Ward Syndrome / Q000235:genetics*; D012720:Severity of Illness Index; D013019:South Africa; D055815:Young Adult
chemical_list: D054758:A Kinase Anchor Proteins; C119719:AKAP9 protein, human; D003598:Cytoskeletal Proteins
keywords: AKAP9; KCNQ1; arrhythmia; long-QT syndrome
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