title: Common miR-590 Variant rs6971711 Present Only in African Americans Reduces miR-590 Biogenesis.
abstract: MicroRNAs (miRNAs) are recognized as important regulators of cardiac development, hypertrophy and fibrosis. Recent studies have demonstrated that genetic variations which cause alterations in miRNA:target interactions can lead to disease. We hypothesized that genetic variations in miRNAs that regulate cardiac hypertrophy/fibrosis might be involved in generation of the cardiac phenotype in patients diagnosed with hypertrophic cardiomyopathy (HCM). To investigate this question, we Sanger sequenced 18 miRNA genes previously implicated in myocyte hypertrophy/fibrosis and apoptosis, using genomic DNA isolated from the leukocytes of 199 HCM patients. We identified a single nucleotide polymorphism (rs6971711, C57T SNP) at the 17th position of mature miR-590-3p (= 57th position of pre-miR-590) that is common in individuals of African ancestry. SNP frequency was higher in African American HCM patients (n = 55) than ethnically-matched controls (n = 100), but the difference was not statistically significant (8.2% vs. 6.5%; p = 0.5). Using a cell culture system, we discovered that presence of this SNP resulted in markedly lower levels of mature miR-590-5p (39 ± 16%, p<0.003) and miR-590-3p (20 ± 2%, p<0.003), when compared with wild-type (WT) miR-590, without affecting levels of pri-miR-590 and pre-miR-590. Consistent with this finding, the SNP resulted in reduced target suppression when compared to WT miR-590 (71% suppression by WT vs 60% suppression by SNP, p<0.03). Since miR-590 can regulate TGF-β, Activin A and Akt signaling, SNP-induced reduction in miR-590 biogenesis could influence cardiac phenotype by de-repression of these signaling pathways. Since the SNP is only present in African Americans, population studies in this patient population would be valuable to investigate effects of this SNP on myocyte function and cardiac physiology.
authors.affiliation: Hypertrophic Cardiomyopathy Center of Excellence, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.|Department of Cardiology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Lin
authors.affiliation: Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.
authors.forename: Steven
authors.initials: S
authors.lastname: Steinberg
authors.affiliation: Department of Biological Chemistry, Johns Hopkins School of Medicine, Baltimore, MD, United States of America.
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Kandasamy
authors.affiliation: Hypertrophic Cardiomyopathy Center of Excellence, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.
authors.forename: Junaid
authors.initials: J
authors.lastname: Afzal
authors.affiliation: Hypertrophic Cardiomyopathy Center of Excellence, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.
authors.forename: Blaid
authors.initials: B
authors.lastname: Mbiyangandu
authors.affiliation: Department of Biological Chemistry, Johns Hopkins School of Medicine, Baltimore, MD, United States of America.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Liao
authors.affiliation: Hypertrophic Cardiomyopathy Center of Excellence, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.
authors.forename: Yufan
authors.initials: Y
authors.lastname: Guan
authors.affiliation: Hypertrophic Cardiomyopathy Center of Excellence, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.
authors.forename: Celia P
authors.initials: CP
authors.lastname: Corona-Villalobos
authors.affiliation: Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, United States of America.
authors.forename: Scot J
authors.initials: SJ
authors.lastname: Matkovich
authors.affiliation: Laboratory of Molecular Cardiology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States of America.
authors.forename: Neal
authors.initials: N
authors.lastname: Epstein
authors.affiliation: Laboratory of Molecular Cardiology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States of America.
authors.forename: Dotti
authors.initials: D
authors.lastname: Tripodi
authors.affiliation: Clinical Research Center, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Zhaoxia
authors.initials: Z
authors.lastname: Huo
authors.affiliation: Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.
authors.forename: Garry
authors.initials: G
authors.lastname: Cutting
authors.affiliation: Hypertrophic Cardiomyopathy Center of Excellence, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.
authors.forename: Theodore P
authors.initials: TP
authors.lastname: Abraham
authors.affiliation: Department of Biological Chemistry, Johns Hopkins School of Medicine, Baltimore, MD, United States of America.
authors.forename: Ryuya
authors.identifier: 0000-0002-5814-8206
authors.initials: R
authors.lastname: Fukunaga
authors.affiliation: Hypertrophic Cardiomyopathy Center of Excellence, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.
authors.forename: M Roselle
authors.initials: MR
authors.lastname: Abraham
mesh_terms: D001741:Black or African American / Q000235:genetics*; D002312:Cardiomyopathy, Hypertrophic / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D057809:HEK293 Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D020641:Polymorphism, Single Nucleotide
chemical_list: C568221:MIRN590 microRNA, human; D035683:MicroRNAs