{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T21:58:54Z","timestamp":1771624734445,"version":"3.50.1"},"reference-count":41,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2018,3]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>\n              Inhibition of PKC-\u03b1 (protein kinase C-\u03b1) enhances contractility and cardioprotection in animal models, but effects in humans are unknown. Genotypes at rs9912468 strongly associate with\n              <jats:italic>PRKCA<\/jats:italic>\n              expression in the left ventricle, enabling genetic approaches to measure effects of reduced PKC-\u03b1 in human populations.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results:<\/jats:title>\n            <jats:p>\n              We analyzed the\n              <jats:italic>cis<\/jats:italic>\n              expression quantitative trait locus for\n              <jats:italic>PRKCA<\/jats:italic>\n              marked by rs9912468 using 313 left ventricular specimens from European Ancestry patients. The forward strand minor allele (G) at rs9912468 is associated with reduced PKC-\u03b1 transcript abundance (1.7-fold reduction in minor allele homozygotes,\n              <jats:italic>P<\/jats:italic>\n              =1\u00d710\n              <jats:sup>\u221241<\/jats:sup>\n              ). This association was cardiac specific in expression quantitative trait locus data sets that span 16 human tissues. Cardiac epigenomic data revealed a predicted enhancer in complete (\n              <jats:italic>R<\/jats:italic>\n              <jats:sup>2<\/jats:sup>\n              =1.0) linkage disequilibrium with rs9912468 within intron 2 of\n              <jats:italic>PRKCA.<\/jats:italic>\n              We cloned this region and used reporter constructs to verify cardiac-specific enhancer activity in vitro in cardiac and noncardiac cells and in vivo in zebrafish. The\n              <jats:italic>PRKCA<\/jats:italic>\n              enhancer contains 2 common genetic variants and 4 haplotypes; the haplotype correlated with the rs9912468 PKC-\u03b1\u2013lowering allele (G) showed lowest activity. In contrast to previous reports in animal models, the PKC-\u03b1\u2013lowering allele is associated with adverse left ventricular remodeling (higher mass, larger diastolic dimension), reduced fractional shortening, and higher risk of dilated cardiomyopathy in human populations.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>These findings support PKC-\u03b1 as a regulator of the human heart but suggest that PKC-\u03b1 inhibition may adversely affect the left ventricle depending on timing and duration. Pharmacological studies in human subjects are required to discern potential benefits and harms of PKC-\u03b1 inhibitors as an approach to treat heart disease.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgen.117.001901","type":"journal-article","created":{"date-parts":[[2018,10,9]],"date-time":"2018-10-09T08:02:20Z","timestamp":1539072140000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":15,"title":["Genetic Reduction in Left Ventricular Protein Kinase C-\u03b1 and Adverse Ventricular Remodeling in Human Subjects"],"prefix":"10.1161","volume":"11","author":[{"given":"Ray","family":"Hu","sequence":"first","affiliation":[{"name":"From the Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.H., M.P.M., J.B., K.B.M., T.P.C.); Cardiovascular Research Center (N.R.T., V.A.P., P.T.E.) and Center for Human Genetic Research and Cardiovascular Research Center (C.N.-C.), Massachusetts General Hospital, Boston; Department of Statistics, University of Illinois at Urbana\u2013Champaign (S.D.Z.); Heidelberg University Hospital, Germany (B.M., H.A.K.); Department of Genetic Epidemiology,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael P.","family":"Morley","sequence":"additional","affiliation":[{"name":"From the Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.H., M.P.M., J.B., K.B.M., T.P.C.); Cardiovascular Research Center (N.R.T., V.A.P., P.T.E.) and Center for Human Genetic Research and Cardiovascular Research Center (C.N.-C.), Massachusetts General Hospital, Boston; Department of Statistics, University of Illinois at Urbana\u2013Champaign (S.D.Z.); Heidelberg University Hospital, Germany (B.M., H.A.K.); Department of Genetic Epidemiology,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey","family":"Brandimarto","sequence":"additional","affiliation":[{"name":"From the Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.H., M.P.M., J.B., K.B.M., T.P.C.); Cardiovascular Research Center (N.R.T., V.A.P., P.T.E.) and Center for Human Genetic Research and Cardiovascular Research Center (C.N.-C.), Massachusetts General Hospital, Boston; Department of Statistics, University of Illinois at Urbana\u2013Champaign (S.D.Z.); Heidelberg University Hospital, Germany (B.M., H.A.K.); Department of Genetic Epidemiology,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nathan R.","family":"Tucker","sequence":"additional","affiliation":[{"name":"From the Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.H., M.P.M., J.B., K.B.M., T.P.C.); Cardiovascular Research Center (N.R.T., V.A.P., P.T.E.) and Center for Human Genetic Research and Cardiovascular Research Center (C.N.-C.), Massachusetts General Hospital, Boston; Department of Statistics, University of Illinois at Urbana\u2013Champaign (S.D.Z.); Heidelberg University Hospital, Germany (B.M., H.A.K.); Department of Genetic Epidemiology,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victoria A.","family":"Parsons","sequence":"additional","affiliation":[{"name":"From the Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.H., M.P.M., J.B., K.B.M., T.P.C.); Cardiovascular Research Center (N.R.T., V.A.P., P.T.E.) and Center for Human Genetic Research and Cardiovascular Research Center (C.N.-C.), Massachusetts General Hospital, Boston; Department of Statistics, University of Illinois at Urbana\u2013Champaign (S.D.Z.); Heidelberg University Hospital, Germany (B.M., H.A.K.); Department of Genetic Epidemiology,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sihai D.","family":"Zhao","sequence":"additional","affiliation":[{"name":"From the Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.H., M.P.M., J.B., K.B.M., T.P.C.); Cardiovascular Research Center (N.R.T., V.A.P., P.T.E.) and Center for Human Genetic Research and Cardiovascular Research Center (C.N.-C.), Massachusetts General Hospital, Boston; Department of Statistics, University of Illinois at Urbana\u2013Champaign (S.D.Z.); Heidelberg University Hospital, Germany (B.M., H.A.K.); Department of Genetic Epidemiology,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin","family":"Meder","sequence":"additional","affiliation":[{"name":"From the Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.H., M.P.M., J.B., K.B.M., T.P.C.); Cardiovascular Research Center (N.R.T., V.A.P., P.T.E.) and Center for Human Genetic Research and Cardiovascular Research Center (C.N.-C.), Massachusetts General Hospital, Boston; Department of Statistics, University of Illinois at Urbana\u2013Champaign (S.D.Z.); Heidelberg University Hospital, Germany (B.M., H.A.K.); Department of Genetic Epidemiology,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hugo A.","family":"Katus","sequence":"additional","affiliation":[{"name":"From the Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.H., M.P.M., J.B., K.B.M., T.P.C.); Cardiovascular Research Center (N.R.T., V.A.P., P.T.E.) and Center for Human Genetic Research and Cardiovascular Research Center (C.N.-C.), Massachusetts General Hospital, Boston; Department of Statistics, University of Illinois at Urbana\u2013Champaign (S.D.Z.); Heidelberg University Hospital, Germany (B.M., H.A.K.); Department of Genetic Epidemiology,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank","family":"R\u00fchle","sequence":"additional","affiliation":[{"name":"From the Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.H., M.P.M., J.B., K.B.M., T.P.C.); Cardiovascular Research Center (N.R.T., V.A.P., P.T.E.) and Center for Human Genetic Research and Cardiovascular Research Center (C.N.-C.), Massachusetts General Hospital, Boston; Department of Statistics, University of Illinois at Urbana\u2013Champaign (S.D.Z.); Heidelberg University Hospital, Germany (B.M., H.A.K.); Department of Genetic Epidemiology,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monika","family":"Stoll","sequence":"additional","affiliation":[{"name":"From the Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.H., M.P.M., J.B., K.B.M., T.P.C.); Cardiovascular Research Center (N.R.T., V.A.P., P.T.E.) and Center for Human Genetic Research and Cardiovascular Research Center (C.N.-C.), Massachusetts General Hospital, Boston; Department of Statistics, University of Illinois at Urbana\u2013Champaign (S.D.Z.); Heidelberg University Hospital, Germany (B.M., H.A.K.); Department of Genetic Epidemiology,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric","family":"Villard","sequence":"additional","affiliation":[{"name":"From the Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.H., M.P.M., J.B., K.B.M., T.P.C.); Cardiovascular Research Center (N.R.T., V.A.P., P.T.E.) and Center for Human Genetic Research and Cardiovascular Research Center (C.N.-C.), Massachusetts General Hospital, Boston; Department of Statistics, University of Illinois at Urbana\u2013Champaign (S.D.Z.); Heidelberg University Hospital, Germany (B.M., H.A.K.); Department of Genetic Epidemiology,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fran\u00e7ois","family":"Cambien","sequence":"additional","affiliation":[{"name":"From the Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.H., M.P.M., J.B., K.B.M., T.P.C.); Cardiovascular Research Center (N.R.T., V.A.P., P.T.E.) and Center for Human Genetic Research and Cardiovascular Research Center (C.N.-C.), Massachusetts General Hospital, Boston; Department of Statistics, University of Illinois at Urbana\u2013Champaign (S.D.Z.); Heidelberg University Hospital, Germany (B.M., H.A.K.); Department of Genetic Epidemiology,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Honghuang","family":"Lin","sequence":"additional","affiliation":[{"name":"From the Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.H., M.P.M., J.B., K.B.M., T.P.C.); Cardiovascular Research Center (N.R.T., V.A.P., P.T.E.) and Center for Human Genetic Research and Cardiovascular Research Center (C.N.-C.), Massachusetts General Hospital, Boston; Department of Statistics, University of Illinois at Urbana\u2013Champaign (S.D.Z.); Heidelberg University Hospital, Germany (B.M., H.A.K.); Department of Genetic Epidemiology,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas L.","family":"Smith","sequence":"additional","affiliation":[{"name":"From the Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.H., M.P.M., J.B., K.B.M., T.P.C.); Cardiovascular Research Center (N.R.T., V.A.P., P.T.E.) and Center for Human Genetic Research and Cardiovascular Research Center (C.N.-C.), Massachusetts General Hospital, Boston; Department of Statistics, University of Illinois at Urbana\u2013Champaign (S.D.Z.); Heidelberg University Hospital, Germany (B.M., H.A.K.); Department of Genetic Epidemiology,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janine F.","family":"Felix","sequence":"additional","affiliation":[{"name":"From the Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.H., M.P.M., J.B., K.B.M., T.P.C.); Cardiovascular Research Center (N.R.T., V.A.P., P.T.E.) and Center for Human Genetic Research and Cardiovascular Research Center (C.N.-C.), Massachusetts General Hospital, Boston; Department of Statistics, University of Illinois at Urbana\u2013Champaign (S.D.Z.); Heidelberg University Hospital, Germany (B.M., H.A.K.); Department of Genetic Epidemiology,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ramachandran S.","family":"Vasan","sequence":"additional","affiliation":[{"name":"From the Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.H., M.P.M., J.B., K.B.M., T.P.C.); Cardiovascular Research Center (N.R.T., V.A.P., P.T.E.) and Center for Human Genetic Research and Cardiovascular Research Center (C.N.-C.), Massachusetts General Hospital, Boston; Department of Statistics, University of Illinois at Urbana\u2013Champaign (S.D.Z.); Heidelberg University Hospital, Germany (B.M., H.A.K.); Department of Genetic Epidemiology,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pim","family":"van der Harst","sequence":"additional","affiliation":[{"name":"From the Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.H., M.P.M., J.B., K.B.M., T.P.C.); Cardiovascular Research Center (N.R.T., V.A.P., P.T.E.) and Center for Human Genetic Research and Cardiovascular Research Center (C.N.-C.), Massachusetts General Hospital, Boston; Department of Statistics, University of Illinois at Urbana\u2013Champaign (S.D.Z.); Heidelberg University Hospital, Germany (B.M., H.A.K.); Department of Genetic Epidemiology,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher","family":"Newton-Cheh","sequence":"additional","affiliation":[{"name":"From the Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.H., M.P.M., J.B., K.B.M., T.P.C.); Cardiovascular Research Center (N.R.T., V.A.P., P.T.E.) and Center for Human Genetic Research and Cardiovascular Research Center (C.N.-C.), Massachusetts General Hospital, Boston; Department of Statistics, University of Illinois at Urbana\u2013Champaign (S.D.Z.); Heidelberg University Hospital, Germany (B.M., H.A.K.); Department of Genetic Epidemiology,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jin","family":"Li","sequence":"additional","affiliation":[{"name":"From the Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.H., M.P.M., J.B., K.B.M., T.P.C.); Cardiovascular Research Center (N.R.T., V.A.P., P.T.E.) and Center for Human Genetic Research and Cardiovascular Research Center (C.N.-C.), Massachusetts General Hospital, Boston; Department of Statistics, University of Illinois at Urbana\u2013Champaign (S.D.Z.); Heidelberg University Hospital, Germany (B.M., H.A.K.); Department of Genetic Epidemiology,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cecilia E.","family":"Kim","sequence":"additional","affiliation":[{"name":"From the Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.H., M.P.M., J.B., K.B.M., T.P.C.); Cardiovascular Research Center (N.R.T., V.A.P., P.T.E.) and Center for Human Genetic Research and Cardiovascular Research Center (C.N.-C.), Massachusetts General Hospital, Boston; Department of Statistics, University of Illinois at Urbana\u2013Champaign (S.D.Z.); Heidelberg University Hospital, Germany (B.M., H.A.K.); Department of Genetic Epidemiology,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hakon","family":"Hakonarson","sequence":"additional","affiliation":[{"name":"From the Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.H., M.P.M., J.B., K.B.M., T.P.C.); Cardiovascular Research Center (N.R.T., V.A.P., P.T.E.) and Center for Human Genetic Research and Cardiovascular Research Center (C.N.-C.), Massachusetts General Hospital, Boston; Department of Statistics, University of Illinois at Urbana\u2013Champaign (S.D.Z.); Heidelberg University Hospital, Germany (B.M., H.A.K.); Department of Genetic Epidemiology,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sridhar","family":"Hannenhalli","sequence":"additional","affiliation":[{"name":"From the Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.H., M.P.M., J.B., K.B.M., T.P.C.); Cardiovascular Research Center (N.R.T., V.A.P., P.T.E.) and Center for Human Genetic Research and Cardiovascular Research Center (C.N.-C.), Massachusetts General Hospital, Boston; Department of Statistics, University of Illinois at Urbana\u2013Champaign (S.D.Z.); Heidelberg University Hospital, Germany (B.M., H.A.K.); Department of Genetic Epidemiology,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Euan A.","family":"Ashley","sequence":"additional","affiliation":[{"name":"From the Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.H., M.P.M., J.B., K.B.M., T.P.C.); Cardiovascular Research Center (N.R.T., V.A.P., P.T.E.) and Center for Human Genetic Research and Cardiovascular Research Center (C.N.-C.), Massachusetts General Hospital, Boston; Department of Statistics, University of Illinois at Urbana\u2013Champaign (S.D.Z.); Heidelberg University Hospital, Germany (B.M., H.A.K.); Department of Genetic Epidemiology,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christine S.","family":"Moravec","sequence":"additional","affiliation":[{"name":"From the Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.H., M.P.M., J.B., K.B.M., T.P.C.); Cardiovascular Research Center (N.R.T., V.A.P., P.T.E.) and Center for Human Genetic Research and Cardiovascular Research Center (C.N.-C.), Massachusetts General Hospital, Boston; Department of Statistics, University of Illinois at Urbana\u2013Champaign (S.D.Z.); Heidelberg University Hospital, Germany (B.M., H.A.K.); Department of Genetic Epidemiology,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"W.H. Wilson","family":"Tang","sequence":"additional","affiliation":[{"name":"From the Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.H., M.P.M., J.B., K.B.M., T.P.C.); Cardiovascular Research Center (N.R.T., V.A.P., P.T.E.) and Center for Human Genetic Research and Cardiovascular Research Center (C.N.-C.), Massachusetts General Hospital, Boston; Department of Statistics, University of Illinois at Urbana\u2013Champaign (S.D.Z.); Heidelberg University Hospital, Germany (B.M., H.A.K.); Department of Genetic Epidemiology,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marjorie","family":"Maillet","sequence":"additional","affiliation":[{"name":"From the Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.H., M.P.M., J.B., K.B.M., T.P.C.); Cardiovascular Research Center (N.R.T., V.A.P., P.T.E.) and Center for Human Genetic Research and Cardiovascular Research Center (C.N.-C.), Massachusetts General Hospital, Boston; Department of Statistics, University of Illinois at Urbana\u2013Champaign (S.D.Z.); Heidelberg University Hospital, Germany (B.M., H.A.K.); Department of Genetic Epidemiology,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffery D.","family":"Molkentin","sequence":"additional","affiliation":[{"name":"From the Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.H., M.P.M., J.B., K.B.M., T.P.C.); Cardiovascular Research Center (N.R.T., V.A.P., P.T.E.) and Center for Human Genetic Research and Cardiovascular Research Center (C.N.-C.), Massachusetts General Hospital, Boston; Department of Statistics, University of Illinois at Urbana\u2013Champaign (S.D.Z.); Heidelberg University Hospital, Germany (B.M., H.A.K.); Department of Genetic Epidemiology,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick T.","family":"Ellinor","sequence":"additional","affiliation":[{"name":"From the Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.H., M.P.M., J.B., K.B.M., T.P.C.); Cardiovascular Research Center (N.R.T., V.A.P., P.T.E.) and Center for Human Genetic Research and Cardiovascular Research Center (C.N.-C.), Massachusetts General Hospital, Boston; Department of Statistics, University of Illinois at Urbana\u2013Champaign (S.D.Z.); Heidelberg University Hospital, Germany (B.M., H.A.K.); Department of Genetic Epidemiology,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenneth B.","family":"Margulies","sequence":"additional","affiliation":[{"name":"From the Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.H., M.P.M., J.B., K.B.M., T.P.C.); Cardiovascular Research Center (N.R.T., V.A.P., P.T.E.) and Center for Human Genetic Research and Cardiovascular Research Center (C.N.-C.), Massachusetts General Hospital, Boston; Department of Statistics, University of Illinois at Urbana\u2013Champaign (S.D.Z.); Heidelberg University Hospital, Germany (B.M., H.A.K.); Department of Genetic Epidemiology,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas P","family":"Cappola","sequence":"additional","affiliation":[{"name":"From the Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.H., M.P.M., J.B., K.B.M., T.P.C.); 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