title: Stroke and Circulating Extracellular RNAs.
abstract: There is increasing interest in extracellular RNAs (ex-RNAs), with numerous reports of associations between selected microRNAs (miRNAs) and a variety of cardiovascular disease phenotypes. Previous studies of ex-RNAs in relation to risk for cardiovascular disease have investigated small numbers of patients and assayed only candidate miRNAs. No human studies have investigated links between novel ex-RNAs and stroke.
  
  
  
  We conducted unbiased next-generation sequencing using plasma from 40 participants of the FHS (Framingham Heart Study; Offspring Cohort Exam 8) followed by high-throughput polymerase chain reaction of 471 ex-RNAs. The reverse transcription quantitative polymerase chain reaction included 331 of the most abundant miRNAs, 43 small nucleolar RNAs, and 97 piwi-interacting RNAs in 2763 additional FHS participants and explored the relations of ex-RNAs and prevalent (n=63) and incident (n=51) stroke and coronary heart disease (prevalent=286, incident=69).
  
  
  
  After adjustment for multiple cardiovascular disease risk factors, 7 ex-RNAs were associated with stroke prevalence or incidence; there were no ex-RNA associated with prevalent or incident coronary heart disease. Statistically significant ex-RNA associations with stroke were specific, with no overlap between prevalent and incident events.
  
  
  
  This is the largest study of ex-RNAs in relation to stroke using an unbiased approach in an observational cohort and the first large study to examine human small noncoding RNAs beyond miRNAs. These results demonstrate that when studied in a large observational cohort, extracellular miRNAs are associated with stroke risk.
authors.affiliation: From the Department of Quantitative Health Sciences (E.M.) and Department of Medicine (K.T., J.E.F.), University of Massachusetts Medical School, Worcester; Department of Cardiology, Massachusetts General Hospital, Boston (R.S.); Department of Cardiology, University of Michigan, Ann Arbor (V.M.); Yale University Medical School, Computational Biology, New Haven, CT (M.G., J.R., R.K.); The NHLBI's and Boston University's Framingham Heart Study, MA (M.G.L.); Biostatistics Department, Boston University School of Public Health, MA (M.G.L.); and The Framingham Heart Study, Population Sciences Branch, NHLBI, Bethesda, MD (D.L.).
authors.forename: Eric
authors.initials: E
authors.lastname: Mick
authors.affiliation: From the Department of Quantitative Health Sciences (E.M.) and Department of Medicine (K.T., J.E.F.), University of Massachusetts Medical School, Worcester; Department of Cardiology, Massachusetts General Hospital, Boston (R.S.); Department of Cardiology, University of Michigan, Ann Arbor (V.M.); Yale University Medical School, Computational Biology, New Haven, CT (M.G., J.R., R.K.); The NHLBI's and Boston University's Framingham Heart Study, MA (M.G.L.); Biostatistics Department, Boston University School of Public Health, MA (M.G.L.); and The Framingham Heart Study, Population Sciences Branch, NHLBI, Bethesda, MD (D.L.).
authors.forename: Ravi
authors.initials: R
authors.lastname: Shah
authors.affiliation: From the Department of Quantitative Health Sciences (E.M.) and Department of Medicine (K.T., J.E.F.), University of Massachusetts Medical School, Worcester; Department of Cardiology, Massachusetts General Hospital, Boston (R.S.); Department of Cardiology, University of Michigan, Ann Arbor (V.M.); Yale University Medical School, Computational Biology, New Haven, CT (M.G., J.R., R.K.); The NHLBI's and Boston University's Framingham Heart Study, MA (M.G.L.); Biostatistics Department, Boston University School of Public Health, MA (M.G.L.); and The Framingham Heart Study, Population Sciences Branch, NHLBI, Bethesda, MD (D.L.).
authors.forename: Kahraman
authors.initials: K
authors.lastname: Tanriverdi
authors.affiliation: From the Department of Quantitative Health Sciences (E.M.) and Department of Medicine (K.T., J.E.F.), University of Massachusetts Medical School, Worcester; Department of Cardiology, Massachusetts General Hospital, Boston (R.S.); Department of Cardiology, University of Michigan, Ann Arbor (V.M.); Yale University Medical School, Computational Biology, New Haven, CT (M.G., J.R., R.K.); The NHLBI's and Boston University's Framingham Heart Study, MA (M.G.L.); Biostatistics Department, Boston University School of Public Health, MA (M.G.L.); and The Framingham Heart Study, Population Sciences Branch, NHLBI, Bethesda, MD (D.L.).
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Murthy
authors.affiliation: From the Department of Quantitative Health Sciences (E.M.) and Department of Medicine (K.T., J.E.F.), University of Massachusetts Medical School, Worcester; Department of Cardiology, Massachusetts General Hospital, Boston (R.S.); Department of Cardiology, University of Michigan, Ann Arbor (V.M.); Yale University Medical School, Computational Biology, New Haven, CT (M.G., J.R., R.K.); The NHLBI's and Boston University's Framingham Heart Study, MA (M.G.L.); Biostatistics Department, Boston University School of Public Health, MA (M.G.L.); and The Framingham Heart Study, Population Sciences Branch, NHLBI, Bethesda, MD (D.L.).
authors.forename: Mark
authors.initials: M
authors.lastname: Gerstein
authors.affiliation: From the Department of Quantitative Health Sciences (E.M.) and Department of Medicine (K.T., J.E.F.), University of Massachusetts Medical School, Worcester; Department of Cardiology, Massachusetts General Hospital, Boston (R.S.); Department of Cardiology, University of Michigan, Ann Arbor (V.M.); Yale University Medical School, Computational Biology, New Haven, CT (M.G., J.R., R.K.); The NHLBI's and Boston University's Framingham Heart Study, MA (M.G.L.); Biostatistics Department, Boston University School of Public Health, MA (M.G.L.); and The Framingham Heart Study, Population Sciences Branch, NHLBI, Bethesda, MD (D.L.).
authors.forename: Joel
authors.initials: J
authors.lastname: Rozowsky
authors.affiliation: From the Department of Quantitative Health Sciences (E.M.) and Department of Medicine (K.T., J.E.F.), University of Massachusetts Medical School, Worcester; Department of Cardiology, Massachusetts General Hospital, Boston (R.S.); Department of Cardiology, University of Michigan, Ann Arbor (V.M.); Yale University Medical School, Computational Biology, New Haven, CT (M.G., J.R., R.K.); The NHLBI's and Boston University's Framingham Heart Study, MA (M.G.L.); Biostatistics Department, Boston University School of Public Health, MA (M.G.L.); and The Framingham Heart Study, Population Sciences Branch, NHLBI, Bethesda, MD (D.L.).
authors.forename: Robert
authors.initials: R
authors.lastname: Kitchen
authors.affiliation: From the Department of Quantitative Health Sciences (E.M.) and Department of Medicine (K.T., J.E.F.), University of Massachusetts Medical School, Worcester; Department of Cardiology, Massachusetts General Hospital, Boston (R.S.); Department of Cardiology, University of Michigan, Ann Arbor (V.M.); Yale University Medical School, Computational Biology, New Haven, CT (M.G., J.R., R.K.); The NHLBI's and Boston University's Framingham Heart Study, MA (M.G.L.); Biostatistics Department, Boston University School of Public Health, MA (M.G.L.); and The Framingham Heart Study, Population Sciences Branch, NHLBI, Bethesda, MD (D.L.).
authors.forename: Martin G
authors.initials: MG
authors.lastname: Larson
authors.affiliation: From the Department of Quantitative Health Sciences (E.M.) and Department of Medicine (K.T., J.E.F.), University of Massachusetts Medical School, Worcester; Department of Cardiology, Massachusetts General Hospital, Boston (R.S.); Department of Cardiology, University of Michigan, Ann Arbor (V.M.); Yale University Medical School, Computational Biology, New Haven, CT (M.G., J.R., R.K.); The NHLBI's and Boston University's Framingham Heart Study, MA (M.G.L.); Biostatistics Department, Boston University School of Public Health, MA (M.G.L.); and The Framingham Heart Study, Population Sciences Branch, NHLBI, Bethesda, MD (D.L.).
authors.forename: Daniel
authors.initials: D
authors.lastname: Levy
authors.affiliation: From the Department of Quantitative Health Sciences (E.M.) and Department of Medicine (K.T., J.E.F.), University of Massachusetts Medical School, Worcester; Department of Cardiology, Massachusetts General Hospital, Boston (R.S.); Department of Cardiology, University of Michigan, Ann Arbor (V.M.); Yale University Medical School, Computational Biology, New Haven, CT (M.G., J.R., R.K.); The NHLBI's and Boston University's Framingham Heart Study, MA (M.G.L.); Biostatistics Department, Boston University School of Public Health, MA (M.G.L.); and The Framingham Heart Study, Population Sciences Branch, NHLBI, Bethesda, MD (D.L.). jane.freedman@umassmed.edu.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Freedman
mesh_terms: D000368:Aged; D015331:Cohort Studies; D003327:Coronary Disease / Q000097:blood* / Q000453:epidemiology; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015994:Incidence; D008297:Male; D008404:Massachusetts / Q000453:epidemiology; D035683:MicroRNAs / Q000097:blood*; D008875:Middle Aged; D015995:Prevalence; D034741:RNA, Small Interfering / Q000097:blood*; D020537:RNA, Small Nucleolar / Q000097:blood*; D020521:Stroke / Q000097:blood* / Q000453:epidemiology
chemical_list: D035683:MicroRNAs; D034741:RNA, Small Interfering; D020537:RNA, Small Nucleolar
keywords: RNAs; cardiovascular diseases; genes; risk factors; stroke