Evidence map›Paper›PMID 25087618›Full record

ArticleCirculation. Cardiovascular genetics2014

AKAP9 is a genetic modifier of congenital long-QT syndrome type 1.

Carin P de Villiers, Lize van der Merwe, Lia Crotti, Althea Goosen, Alfred L George, Peter J Schwartz, Paul A Brink, Johanna C Moolman-Smook, Valerie A Corfield

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In one paragraph

Article in Circulation. Cardiovascular genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.

0numbers the graph read from it
0cells of the map it votes in
38citing papers in PubMed
4.1field-weighted citation impact, top 5% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

38 citing papers in PubMed, 70 citations in OpenAlex.

  1. An Unusual Genetic Variant of Long QT Syndrome with Late Presentation in the Sixth Decade.The Journal of innovations in cardiac rhythm management · 2026
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  2. Functional Profiling ofCirculation. Genomic and precision medicine · 2025
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  7. A Novel Variant inMolecular syndromology · 2024
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

9 authors at 3 institutions in 2 countries.

Carin P de VilliersFrom 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.).
Lize van der MerweFrom 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.).
Lia CrottiFrom 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.).
Althea GoosenFrom 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.).
Alfred L GeorgeFrom 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.).
Peter J SchwartzFrom 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.).
Paul A BrinkFrom 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.).
Johanna C Moolman-SmookFrom 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.).
Valerie A CorfieldFrom 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.).
Istituti di Ricovero e Cura a Carattere Scientifico · ITUniversity of Pavia · ITIRCCS Istituto Auxologico Italiano · IT

Funding

Genetic Modifiers of Congenital Long QT SyndromeR01HL068880 · NHLBI · VANDERBILT UNIVERSITY · PI GEORGE, ALFRED L. · 2001 to 2011
$4.8M
NHLBI NIH HHS HL068880NHLBI NIH HHS R01 HL068880Telethon GGP07016
6 · The paper itself

Abstract

backgroundLong-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. METHODS AND

resultsMembers 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).

conclusionsAKAP9 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.

Indexed as

Genetic Predisposition to DiseaseAdolescentAdultA Kinase Anchor ProteinsAllelesCytoskeletal ProteinsDNA Mutational AnalysisFemaleFounder EffectGenotypeHeterozygoteHumansLeukocytesMaleMiddle AgedModels, GeneticAKAP9 protein, humanA Kinase Anchor ProteinsCytoskeletal ProteinsAKAP9arrhythmiaKCNQ1long-QT syndrome

Identifiers

PMID25087618
PMCPMC4270884
OpenAlexW1976435807

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