{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T20:52:28Z","timestamp":1783630348947,"version":"3.55.0"},"reference-count":40,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"24","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2026,6,16]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Individuals of African ancestry are underrepresented in genetic studies, contributing to disproportionately higher rates of variants of uncertain significance (VUS) and fewer actionable results in genetic testing for cardiomyopathies and arrhythmias. We aimed to determine whether ancestry-enriched VUS confer measurable cardiovascular risk among individuals of African ancestry.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>We identified VUS enriched in individuals of African ancestry in 18 cardiomyopathy and arrhythmia genes. We defined enriched as allele frequency in gnomAD \u22652-fold higher than in European (non-Finnish) individuals, and we confined the analysis to VUS with allele frequency &gt;0.05% in individuals of African ancestry. Associations with cardiovascular phenotypes were assessed in 96\u2009897 individuals of African ancestry from the All of Us (n=65\u2009481) and BioVU (n=31\u2009416) biobanks using fixed-effects meta-analysis. Analyses were stratified by heart failure (HF) status and conventional cardiovascular risk factors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      We identified 82 ancestry-enriched VUS. Exploratory analysis in All of Us identified 10 variants associated with composite cardiovascular outcome, 4 of which were associated with individual cardiovascular phenotypes in pooled meta-analysis across both cohorts.\n                      <jats:italic toggle=\"yes\">PKP2<\/jats:italic>\n                      p.Val558Ile was associated with a 4-fold increased risk of ventricular arrhythmias or sudden cardiac death (adjusted odds ratio [aOR], 4.02 [95% CI, 1.85\u20138.71];\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.004).\n                      <jats:italic toggle=\"yes\">ELAC2<\/jats:italic>\n                      p.Ile396Val was associated with HF (aOR, 1.67 [95% CI, 1.17\u20132.39];\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.02) and atrial arrhythmias (aOR, 1.88 [95% CI, 1.27\u20132.78];\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.02).\n                      <jats:italic toggle=\"yes\">FLNC<\/jats:italic>\n                      p.Gly11Ser and\n                      <jats:italic toggle=\"yes\">PKP2<\/jats:italic>\n                      p.Val842Ile were associated with HF (aOR, 1.96 [95% CI, 1.24\u20133.10];\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.02 and aOR, 1.99 [95% CI, 1.16\u20133.41];\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.039). The presence of cardiovascular risk factors was associated with earlier onset of HF (adjusted hazard ratio, 1.71 [95% CI, 1.25\u20132.33];\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.0006) and atrial arrhythmias (adjusted hazard ratio, 1.17 [95% CI, 1.06\u20131.29];\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.0019) in pooled variant carriers.\n                      <jats:italic toggle=\"yes\">PKP2<\/jats:italic>\n                      p.Val558Ile,\n                      <jats:italic toggle=\"yes\">SCN5A<\/jats:italic>\n                      p.Gln1832Glu, and\n                      <jats:italic toggle=\"yes\">FLNC<\/jats:italic>\n                      p.Gly11Ser demonstrated increased arrhythmia burden specifically in participants with HF. Using American College of Medical Genetics and Genomics guidelines,\n                      <jats:italic toggle=\"yes\">PKP2<\/jats:italic>\n                      p.Val558Ile met criteria for likely pathogenic classification, potentially affecting an estimated 24\u2009000 Black adults in the United States.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Large-scale biobank analysis identified variants classified as VUS that conferred increased risk of cardiomyopathy and arrhythmia in individuals with African ancestry. The risk associated with these variants was increased in the presence of cardiovascular risk factors and HF.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.126.080245","type":"journal-article","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T09:00:42Z","timestamp":1779872442000},"page":"1915-1927","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["Association of Common Ancestry-Enriched Variants With Cardiomyopathy and Arrhythmias"],"prefix":"10.1161","volume":"153","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8371-2000","authenticated-orcid":true,"given":"Temidayo A.","family":"Abe","sequence":"first","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Medicine (T.A.A., M.C.L.), Vanderbilt University Medical Center, Nashville, TN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2697-3762","authenticated-orcid":true,"given":"Megan C.","family":"Lancaster","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Medicine (T.A.A., M.C.L.), Vanderbilt University Medical Center, Nashville, TN."},{"name":"Division of Cardiovascular Medicine, Department of Medicine, The Ohio State University, Columbus (M.C.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6302-0389","authenticated-orcid":true,"given":"Dan M.","family":"Roden","sequence":"additional","affiliation":[{"name":"Departments of Medicine (Genomic Medicine and Clinical Pharmacology), Pharmacology, and Biomedical Informatics (D.M.R.), Vanderbilt University Medical Center, Nashville, 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