{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T23:31:00Z","timestamp":1778801460546,"version":"3.51.4"},"reference-count":47,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ Cardiovasc Genet"],"published-print":{"date-parts":[[2014,10]]},"abstract":"<jats:sec>\n            <jats:title>Background\u2014<\/jats:title>\n            <jats:p>\n              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,\n              <jats:italic>AKAP9<\/jats:italic>\n              , for potential LQTS-type 1\u2013modifying effects.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results\u2014<\/jats:title>\n            <jats:p>\n              Members of a South African LQTS-type 1 founder population (181 noncarriers and 168 mutation carriers) carrying the identical-by-descent\n              <jats:italic>KCNQ1<\/jats:italic>\n              p.Ala341Val (A341V) mutation were evaluated for modifying effects of\n              <jats:italic>AKAP9<\/jats:italic>\n              variants on heart rate\u2013corrected QT interval (QTc), cardiac events, and disease severity. Tag single nucleotide polymorphisms in\n              <jats:italic>AKAP9<\/jats:italic>\n              rs11772585, rs7808587, rs2282972, and rs2961024 (order, 5\u2032-3\u2032positive 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\u2013corrected QT interval increase (1% per additional 10 years) irrespective of A341V mutation status (\n              <jats:italic>P<\/jats:italic>\n              =0.006). The rs11772585 T allele, found uniquely in the TACT haplotype, more than doubled (218%) the risk of cardiac events (\n              <jats:italic>P<\/jats:italic>\n              =0.002) in the presence of A341V; additionally, it increased disease severity (\n              <jats:italic>P<\/jats:italic>\n              =0.025). The rs7808587 GG genotype was associated with a 74% increase in cardiac event risk (\n              <jats:italic>P<\/jats:italic>\n              =0.046), whereas the rs2282972 T allele, predominantly represented by the CATT haplotype, decreased risk by 53% (\n              <jats:italic>P<\/jats:italic>\n              =0.001).\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>\n              <jats:italic>AKAP9<\/jats:italic>\n              has been identified as an LQTS-type 1\u2013modifying gene. Variants investigated altered heart rate\u2013corrected QT interval irrespective of mutation status, as well as cardiac event risk, and disease severity, in mutation carriers.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgenetics.113.000580","type":"journal-article","created":{"date-parts":[[2014,8,4]],"date-time":"2014-08-04T00:07:58Z","timestamp":1407110878000},"page":"599-606","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":65,"title":["<i>AKAP9<\/i>\n            Is a Genetic Modifier of Congenital Long-QT Syndrome Type 1"],"prefix":"10.1161","volume":"7","author":[{"given":"Carin P.","family":"de Villiers","sequence":"first","affiliation":[{"name":"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..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lize","family":"van der Merwe","sequence":"additional","affiliation":[{"name":"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..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lia","family":"Crotti","sequence":"additional","affiliation":[{"name":"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..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Althea","family":"Goosen","sequence":"additional","affiliation":[{"name":"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..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"suffix":"Jr","given":"Alfred L.","family":"George","sequence":"additional","affiliation":[{"name":"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..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter J.","family":"Schwartz","sequence":"additional","affiliation":[{"name":"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..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul A.","family":"Brink","sequence":"additional","affiliation":[{"name":"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..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johanna C.","family":"Moolman-Smook","sequence":"additional","affiliation":[{"name":"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..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valerie A.","family":"Corfield","sequence":"additional","affiliation":[{"name":"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; 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