title: Circulating Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Predicts Future Risk of Cardiovascular Events Independently of Established Risk Factors.
abstract: BACKGROUND
  The secreted protein proprotein convertase subtilisin/kexin type 9 (PCSK9) is a promising new target for lowering plasma low-density lipoprotein cholesterol and preventing cardiovascular disease (CVD). The relationship between circulating PCSK9 and incident CVD in the general population is unknown. We investigated whether serum PCSK9 concentration is associated with incident CVD in a prospective cohort study of 4232 men and women 60 years of age at the time of recruitment.
  
  
  RESULTS
  Incident CVD was recorded by matching to national registries. After 15 years of follow-up, a total of 491 incident events (fatal and nonfatal myocardial infarctions, unstable angina, deaths from coronary heart disease, fatal and nonfatal ischemic strokes) were recorded. Cox proportional hazards model was used to calculate hazard ratios with 95% confidence intervals. Baseline serum PCSK9 concentration predicted incident CVD; concentration in quartile 4 compared with quartile 1 was associated with a hazard ratio of 1.69 (95% confidence interval, 1.30-2.19) after adjustment for sex. Further adjustment for low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, lipoprotein(a), triglycerides, hypertension, diabetes mellitus, smoking, overweight, obesity, physical inactivity, and statin use resulted in a decrease in the hazard ratio to 1.48 (95% confidence interval, 1.12-1.95).
  
  
  CONCLUSIONS
  Serum PCSK9 concentration is associated with future risk of CVD even after adjustments for established CVD risk factors. Further studies are needed to confirm this observation.
authors.affiliation: From the Unit of Cardiovascular Epidemiology, Institute of Environmental Medicine, Stockholm, Sweden (K.L., U.d.F.); Cardiovascular Genetics and Genomics Group, Cardiovascular Medicine Unit, Department of Medicine (A.M., F.M.v.H., J.Ö., A.H.) and Department of Medicine (M.-L.H.), Solna, Karolinska Institutet, Stockholm, Sweden; Pharmatherapeutics Clinical Research, Pfizer Worldwide R&D, Sollentuna, Sweden (A.M.); Research Statistics, Pfizer Worldwide R&D, Cambridge, MA (C.H.); Lilly Research Laboratories, Eli Lilly and Co, Indianapolis, IN (J.S.T., R.J.K.); and Cardiology Unit, Karolinska University Hospital, Stockholm, Sweden (U.d.F.). Karin.Leander@ki.se.
authors.forename: Karin
authors.initials: K
authors.lastname: Leander
authors.affiliation: From the Unit of Cardiovascular Epidemiology, Institute of Environmental Medicine, Stockholm, Sweden (K.L., U.d.F.); Cardiovascular Genetics and Genomics Group, Cardiovascular Medicine Unit, Department of Medicine (A.M., F.M.v.H., J.Ö., A.H.) and Department of Medicine (M.-L.H.), Solna, Karolinska Institutet, Stockholm, Sweden; Pharmatherapeutics Clinical Research, Pfizer Worldwide R&D, Sollentuna, Sweden (A.M.); Research Statistics, Pfizer Worldwide R&D, Cambridge, MA (C.H.); Lilly Research Laboratories, Eli Lilly and Co, Indianapolis, IN (J.S.T., R.J.K.); and Cardiology Unit, Karolinska University Hospital, Stockholm, Sweden (U.d.F.).
authors.forename: Anders
authors.initials: A
authors.lastname: Mälarstig
authors.affiliation: From the Unit of Cardiovascular Epidemiology, Institute of Environmental Medicine, Stockholm, Sweden (K.L., U.d.F.); Cardiovascular Genetics and Genomics Group, Cardiovascular Medicine Unit, Department of Medicine (A.M., F.M.v.H., J.Ö., A.H.) and Department of Medicine (M.-L.H.), Solna, Karolinska Institutet, Stockholm, Sweden; Pharmatherapeutics Clinical Research, Pfizer Worldwide R&D, Sollentuna, Sweden (A.M.); Research Statistics, Pfizer Worldwide R&D, Cambridge, MA (C.H.); Lilly Research Laboratories, Eli Lilly and Co, Indianapolis, IN (J.S.T., R.J.K.); and Cardiology Unit, Karolinska University Hospital, Stockholm, Sweden (U.d.F.).
authors.forename: Ferdinand M
authors.initials: FM
authors.lastname: Van't Hooft
authors.affiliation: From the Unit of Cardiovascular Epidemiology, Institute of Environmental Medicine, Stockholm, Sweden (K.L., U.d.F.); Cardiovascular Genetics and Genomics Group, Cardiovascular Medicine Unit, Department of Medicine (A.M., F.M.v.H., J.Ö., A.H.) and Department of Medicine (M.-L.H.), Solna, Karolinska Institutet, Stockholm, Sweden; Pharmatherapeutics Clinical Research, Pfizer Worldwide R&D, Sollentuna, Sweden (A.M.); Research Statistics, Pfizer Worldwide R&D, Cambridge, MA (C.H.); Lilly Research Laboratories, Eli Lilly and Co, Indianapolis, IN (J.S.T., R.J.K.); and Cardiology Unit, Karolinska University Hospital, Stockholm, Sweden (U.d.F.).
authors.forename: Craig
authors.initials: C
authors.lastname: Hyde
authors.affiliation: From the Unit of Cardiovascular Epidemiology, Institute of Environmental Medicine, Stockholm, Sweden (K.L., U.d.F.); Cardiovascular Genetics and Genomics Group, Cardiovascular Medicine Unit, Department of Medicine (A.M., F.M.v.H., J.Ö., A.H.) and Department of Medicine (M.-L.H.), Solna, Karolinska Institutet, Stockholm, Sweden; Pharmatherapeutics Clinical Research, Pfizer Worldwide R&D, Sollentuna, Sweden (A.M.); Research Statistics, Pfizer Worldwide R&D, Cambridge, MA (C.H.); Lilly Research Laboratories, Eli Lilly and Co, Indianapolis, IN (J.S.T., R.J.K.); and Cardiology Unit, Karolinska University Hospital, Stockholm, Sweden (U.d.F.).
authors.forename: Mai-Lis
authors.initials: ML
authors.lastname: Hellénius
authors.affiliation: From the Unit of Cardiovascular Epidemiology, Institute of Environmental Medicine, Stockholm, Sweden (K.L., U.d.F.); Cardiovascular Genetics and Genomics Group, Cardiovascular Medicine Unit, Department of Medicine (A.M., F.M.v.H., J.Ö., A.H.) and Department of Medicine (M.-L.H.), Solna, Karolinska Institutet, Stockholm, Sweden; Pharmatherapeutics Clinical Research, Pfizer Worldwide R&D, Sollentuna, Sweden (A.M.); Research Statistics, Pfizer Worldwide R&D, Cambridge, MA (C.H.); Lilly Research Laboratories, Eli Lilly and Co, Indianapolis, IN (J.S.T., R.J.K.); and Cardiology Unit, Karolinska University Hospital, Stockholm, Sweden (U.d.F.).
authors.forename: Jason S
authors.initials: JS
authors.lastname: Troutt
authors.affiliation: From the Unit of Cardiovascular Epidemiology, Institute of Environmental Medicine, Stockholm, Sweden (K.L., U.d.F.); Cardiovascular Genetics and Genomics Group, Cardiovascular Medicine Unit, Department of Medicine (A.M., F.M.v.H., J.Ö., A.H.) and Department of Medicine (M.-L.H.), Solna, Karolinska Institutet, Stockholm, Sweden; Pharmatherapeutics Clinical Research, Pfizer Worldwide R&D, Sollentuna, Sweden (A.M.); Research Statistics, Pfizer Worldwide R&D, Cambridge, MA (C.H.); Lilly Research Laboratories, Eli Lilly and Co, Indianapolis, IN (J.S.T., R.J.K.); and Cardiology Unit, Karolinska University Hospital, Stockholm, Sweden (U.d.F.).
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Konrad
authors.affiliation: From the Unit of Cardiovascular Epidemiology, Institute of Environmental Medicine, Stockholm, Sweden (K.L., U.d.F.); Cardiovascular Genetics and Genomics Group, Cardiovascular Medicine Unit, Department of Medicine (A.M., F.M.v.H., J.Ö., A.H.) and Department of Medicine (M.-L.H.), Solna, Karolinska Institutet, Stockholm, Sweden; Pharmatherapeutics Clinical Research, Pfizer Worldwide R&D, Sollentuna, Sweden (A.M.); Research Statistics, Pfizer Worldwide R&D, Cambridge, MA (C.H.); Lilly Research Laboratories, Eli Lilly and Co, Indianapolis, IN (J.S.T., R.J.K.); and Cardiology Unit, Karolinska University Hospital, Stockholm, Sweden (U.d.F.).
authors.forename: John
authors.initials: J
authors.lastname: Öhrvik
authors.affiliation: From the Unit of Cardiovascular Epidemiology, Institute of Environmental Medicine, Stockholm, Sweden (K.L., U.d.F.); Cardiovascular Genetics and Genomics Group, Cardiovascular Medicine Unit, Department of Medicine (A.M., F.M.v.H., J.Ö., A.H.) and Department of Medicine (M.-L.H.), Solna, Karolinska Institutet, Stockholm, Sweden; Pharmatherapeutics Clinical Research, Pfizer Worldwide R&D, Sollentuna, Sweden (A.M.); Research Statistics, Pfizer Worldwide R&D, Cambridge, MA (C.H.); Lilly Research Laboratories, Eli Lilly and Co, Indianapolis, IN (J.S.T., R.J.K.); and Cardiology Unit, Karolinska University Hospital, Stockholm, Sweden (U.d.F.).
authors.forename: Anders
authors.initials: A
authors.lastname: Hamsten
authors.affiliation: From the Unit of Cardiovascular Epidemiology, Institute of Environmental Medicine, Stockholm, Sweden (K.L., U.d.F.); Cardiovascular Genetics and Genomics Group, Cardiovascular Medicine Unit, Department of Medicine (A.M., F.M.v.H., J.Ö., A.H.) and Department of Medicine (M.-L.H.), Solna, Karolinska Institutet, Stockholm, Sweden; Pharmatherapeutics Clinical Research, Pfizer Worldwide R&D, Sollentuna, Sweden (A.M.); Research Statistics, Pfizer Worldwide R&D, Cambridge, MA (C.H.); Lilly Research Laboratories, Eli Lilly and Co, Indianapolis, IN (J.S.T., R.J.K.); and Cardiology Unit, Karolinska University Hospital, Stockholm, Sweden (U.d.F.).
authors.forename: Ulf
authors.initials: U
authors.lastname: de Faire
mesh_terms: D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000097:blood* / Q000175:diagnosis* / Q000453:epidemiology; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000097:blood*; D011446:Prospective Studies; D012042:Registries; D012307:Risk Factors; D012697:Serine Endopeptidases / Q000097:blood*; D013548:Sweden / Q000453:epidemiology
chemical_list: D015415:Biomarkers; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
keywords: biomarkers; cardiovascular diseases; enzymes; epidemiology; follow-up studies