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Original Article

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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https://doi.org/10.1161/CIRCGENETICS.113.000580
Circulation: Genomic and Precision Medicine. 2014;CIRCGENETICS.113.000580
Originally published August 2, 2014
Carin P. de Villiers
Medical Research Council (MRC) Centre for Molecular and Cellular Biology, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa
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  • For correspondence: cpgreen@sun.ac.za
Lize van der Merwe
Medical Research Council (MRC) Centre for Molecular and Cellular Biology, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch & Department of Statistics, University of Western Cape, Bellville, South Africa
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Lia Crotti
IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan & Department of Molecular Medicine, University of Pavia, Pavia, Italy & Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany
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Althea Goosen
Department of Internal Medicine, Stellenbosch University, Stellenbosch, South Africa
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Alfred L. George
Departments of Medicine and Pharmacology & Institute for Integrative Genomics, Vanderbilt University, Nashville, TN
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Peter J. Schwartz
IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy
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Paul A. Brink
Department of Internal Medicine, Stellenbosch University, Stellenbosch, South Africa
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Johanna C. Moolman-Smook
Medical Research Council (MRC) Centre for Molecular and Cellular Biology, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa
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Valerie A. Corfield
Medical Research Council (MRC) Centre for Molecular and Cellular Biology, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa
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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 (LQT1) modifying effects.

Methods and Results—Members of a South African LQT1 founder population (181 non-carriers 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 QTc 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), while the rs2282972 T allele, predominantly represented by the CATT haplotype, decreased risk by 53% (P=0.001).

Conclusions—AKAP9 has been identified as a LQT1-modifying gene. Variants investigated altered QTc irrespective of mutation status, as well as cardiac event risk, and disease severity, in mutation carriers.

  • AKAP9
  • KCNQ1
  • arrhythmia
  • long QT syndrome
  • Received July 8, 2013.
  • Revision received June 6, 2014.
  • Accepted June 22, 2014.
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    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 and Valerie A. Corfield
    Circulation: Genomic and Precision Medicine. 2014;CIRCGENETICS.113.000580, originally published August 2, 2014
    https://doi.org/10.1161/CIRCGENETICS.113.000580

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    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 and Valerie A. Corfield
    Circulation: Genomic and Precision Medicine. 2014;CIRCGENETICS.113.000580, originally published August 2, 2014
    https://doi.org/10.1161/CIRCGENETICS.113.000580
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