title: Variation in PCSK9 and HMGCR and Risk of Cardiovascular Disease and Diabetes.
abstract: Pharmacologic inhibitors of proprotein convertase subtilisin-kexin type 9 (PCSK9) are being evaluated in clinical trials for the treatment of cardiovascular disease. The effect of lowering low-density lipoprotein (LDL) cholesterol levels by inhibiting PCSK9 on the risk of cardiovascular events or diabetes is unknown.
  
  
  
  We used genetic scores consisting of independently inherited variants in the genes encoding PCSK9 and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR; the target of statins) as instruments to randomly assign 112,772 participants from 14 studies, with 14,120 cardiovascular events and 10,635 cases of diabetes, to groups according to the number of LDL cholesterol-lowering alleles that they had inherited. We compared the effects of lower LDL cholesterol levels that were mediated by variants in PCSK9, HMGCR, or both on the risk of cardiovascular events and the risk of diabetes.
  
  
  
  Variants in PCSK9 and HMGCR were associated with nearly identical protective effects on the risk of cardiovascular events per decrease of 10 mg per deciliter (0.26 mmol per liter) in the LDL cholesterol level: odds ratio for cardiovascular events, 0.81 (95% confidence interval [CI], 0.74 to 0.89) for PCSK9 and 0.81 (95% CI, 0.72 to 0.90) for HMGCR. Variants in these two genes were also associated with very similar effects on the risk of diabetes: odds ratio for each 10 mg per deciliter decrease in LDL cholesterol, 1.11 (95% CI, 1.04 to 1.19) for PCSK9 and 1.13 (95% CI, 1.06 to 1.20) for HMGCR. The increased risk of diabetes was limited to persons with impaired fasting glucose levels for both scores and was lower in magnitude than the protective effect against cardiovascular events. When present together, PCSK9 and HMGCR variants had additive effects on the risk of both cardiovascular events and diabetes.
  
  
  
  In this study, variants in PCSK9 had approximately the same effect as variants in HMGCR on the risk of cardiovascular events and diabetes per unit decrease in the LDL cholesterol level. The effects of these variants were independent and additive. (Funded by the Medical Research Council and the National Heart, Lung, and Blood Institute.).
authors.affiliation: From the Division of Cardiovascular Medicine, Wayne State University School of Medicine, Detroit (B.A.F.), the Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor (R.D.B.), and Michigan State University, East Lansing (D.R.N.) - all in Michigan; the Departments of Epidemiology and Medicine, College of Public Health, University of Iowa, Iowa City (J.G.R.); the Department of Pharmacological and Biomolecular Sciences, University of Milan and MultiMedica Istituto di Ricovero e Cura a Carattere Scientifico, Milan (A.L.C.); INSERM, Pitié-Salpêtrière University Hospital, Paris (M.J.C.); the Global Genomics Group, Richmond, VA (S.V.); the Thrombolysis in Myocardial Infarction Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston (R.P.G., M.S.S.); the Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom (G.D.S.); and the Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health and Science University, Portland (S.F.).
authors.forename: Brian A
authors.initials: BA
authors.lastname: Ference
authors.affiliation: From the Division of Cardiovascular Medicine, Wayne State University School of Medicine, Detroit (B.A.F.), the Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor (R.D.B.), and Michigan State University, East Lansing (D.R.N.) - all in Michigan; the Departments of Epidemiology and Medicine, College of Public Health, University of Iowa, Iowa City (J.G.R.); the Department of Pharmacological and Biomolecular Sciences, University of Milan and MultiMedica Istituto di Ricovero e Cura a Carattere Scientifico, Milan (A.L.C.); INSERM, Pitié-Salpêtrière University Hospital, Paris (M.J.C.); the Global Genomics Group, Richmond, VA (S.V.); the Thrombolysis in Myocardial Infarction Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston (R.P.G., M.S.S.); the Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom (G.D.S.); and the Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health and Science University, Portland (S.F.).
authors.forename: Jennifer G
authors.initials: JG
authors.lastname: Robinson
authors.affiliation: From the Division of Cardiovascular Medicine, Wayne State University School of Medicine, Detroit (B.A.F.), the Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor (R.D.B.), and Michigan State University, East Lansing (D.R.N.) - all in Michigan; the Departments of Epidemiology and Medicine, College of Public Health, University of Iowa, Iowa City (J.G.R.); the Department of Pharmacological and Biomolecular Sciences, University of Milan and MultiMedica Istituto di Ricovero e Cura a Carattere Scientifico, Milan (A.L.C.); INSERM, Pitié-Salpêtrière University Hospital, Paris (M.J.C.); the Global Genomics Group, Richmond, VA (S.V.); the Thrombolysis in Myocardial Infarction Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston (R.P.G., M.S.S.); the Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom (G.D.S.); and the Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health and Science University, Portland (S.F.).
authors.forename: Robert D
authors.initials: RD
authors.lastname: Brook
authors.affiliation: From the Division of Cardiovascular Medicine, Wayne State University School of Medicine, Detroit (B.A.F.), the Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor (R.D.B.), and Michigan State University, East Lansing (D.R.N.) - all in Michigan; the Departments of Epidemiology and Medicine, College of Public Health, University of Iowa, Iowa City (J.G.R.); the Department of Pharmacological and Biomolecular Sciences, University of Milan and MultiMedica Istituto di Ricovero e Cura a Carattere Scientifico, Milan (A.L.C.); INSERM, Pitié-Salpêtrière University Hospital, Paris (M.J.C.); the Global Genomics Group, Richmond, VA (S.V.); the Thrombolysis in Myocardial Infarction Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston (R.P.G., M.S.S.); the Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom (G.D.S.); and the Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health and Science University, Portland (S.F.).
authors.forename: Alberico L
authors.initials: AL
authors.lastname: Catapano
authors.affiliation: From the Division of Cardiovascular Medicine, Wayne State University School of Medicine, Detroit (B.A.F.), the Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor (R.D.B.), and Michigan State University, East Lansing (D.R.N.) - all in Michigan; the Departments of Epidemiology and Medicine, College of Public Health, University of Iowa, Iowa City (J.G.R.); the Department of Pharmacological and Biomolecular Sciences, University of Milan and MultiMedica Istituto di Ricovero e Cura a Carattere Scientifico, Milan (A.L.C.); INSERM, Pitié-Salpêtrière University Hospital, Paris (M.J.C.); the Global Genomics Group, Richmond, VA (S.V.); the Thrombolysis in Myocardial Infarction Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston (R.P.G., M.S.S.); the Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom (G.D.S.); and the Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health and Science University, Portland (S.F.).
authors.forename: M John
authors.initials: MJ
authors.lastname: Chapman
authors.affiliation: From the Division of Cardiovascular Medicine, Wayne State University School of Medicine, Detroit (B.A.F.), the Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor (R.D.B.), and Michigan State University, East Lansing (D.R.N.) - all in Michigan; the Departments of Epidemiology and Medicine, College of Public Health, University of Iowa, Iowa City (J.G.R.); the Department of Pharmacological and Biomolecular Sciences, University of Milan and MultiMedica Istituto di Ricovero e Cura a Carattere Scientifico, Milan (A.L.C.); INSERM, Pitié-Salpêtrière University Hospital, Paris (M.J.C.); the Global Genomics Group, Richmond, VA (S.V.); the Thrombolysis in Myocardial Infarction Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston (R.P.G., M.S.S.); the Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom (G.D.S.); and the Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health and Science University, Portland (S.F.).
authors.forename: David R
authors.initials: DR
authors.lastname: Neff
authors.affiliation: From the Division of Cardiovascular Medicine, Wayne State University School of Medicine, Detroit (B.A.F.), the Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor (R.D.B.), and Michigan State University, East Lansing (D.R.N.) - all in Michigan; the Departments of Epidemiology and Medicine, College of Public Health, University of Iowa, Iowa City (J.G.R.); the Department of Pharmacological and Biomolecular Sciences, University of Milan and MultiMedica Istituto di Ricovero e Cura a Carattere Scientifico, Milan (A.L.C.); INSERM, Pitié-Salpêtrière University Hospital, Paris (M.J.C.); the Global Genomics Group, Richmond, VA (S.V.); the Thrombolysis in Myocardial Infarction Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston (R.P.G., M.S.S.); the Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom (G.D.S.); and the Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health and Science University, Portland (S.F.).
authors.forename: Szilard
authors.initials: S
authors.lastname: Voros
authors.affiliation: From the Division of Cardiovascular Medicine, Wayne State University School of Medicine, Detroit (B.A.F.), the Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor (R.D.B.), and Michigan State University, East Lansing (D.R.N.) - all in Michigan; the Departments of Epidemiology and Medicine, College of Public Health, University of Iowa, Iowa City (J.G.R.); the Department of Pharmacological and Biomolecular Sciences, University of Milan and MultiMedica Istituto di Ricovero e Cura a Carattere Scientifico, Milan (A.L.C.); INSERM, Pitié-Salpêtrière University Hospital, Paris (M.J.C.); the Global Genomics Group, Richmond, VA (S.V.); the Thrombolysis in Myocardial Infarction Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston (R.P.G., M.S.S.); the Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom (G.D.S.); and the Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health and Science University, Portland (S.F.).
authors.forename: Robert P
authors.initials: RP
authors.lastname: Giugliano
authors.affiliation: From the Division of Cardiovascular Medicine, Wayne State University School of Medicine, Detroit (B.A.F.), the Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor (R.D.B.), and Michigan State University, East Lansing (D.R.N.) - all in Michigan; the Departments of Epidemiology and Medicine, College of Public Health, University of Iowa, Iowa City (J.G.R.); the Department of Pharmacological and Biomolecular Sciences, University of Milan and MultiMedica Istituto di Ricovero e Cura a Carattere Scientifico, Milan (A.L.C.); INSERM, Pitié-Salpêtrière University Hospital, Paris (M.J.C.); the Global Genomics Group, Richmond, VA (S.V.); the Thrombolysis in Myocardial Infarction Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston (R.P.G., M.S.S.); the Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom (G.D.S.); and the Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health and Science University, Portland (S.F.).
authors.forename: George
authors.initials: G
authors.lastname: Davey Smith
authors.affiliation: From the Division of Cardiovascular Medicine, Wayne State University School of Medicine, Detroit (B.A.F.), the Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor (R.D.B.), and Michigan State University, East Lansing (D.R.N.) - all in Michigan; the Departments of Epidemiology and Medicine, College of Public Health, University of Iowa, Iowa City (J.G.R.); the Department of Pharmacological and Biomolecular Sciences, University of Milan and MultiMedica Istituto di Ricovero e Cura a Carattere Scientifico, Milan (A.L.C.); INSERM, Pitié-Salpêtrière University Hospital, Paris (M.J.C.); the Global Genomics Group, Richmond, VA (S.V.); the Thrombolysis in Myocardial Infarction Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston (R.P.G., M.S.S.); the Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom (G.D.S.); and the Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health and Science University, Portland (S.F.).
authors.forename: Sergio
authors.initials: S
authors.lastname: Fazio
authors.affiliation: From the Division of Cardiovascular Medicine, Wayne State University School of Medicine, Detroit (B.A.F.), the Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor (R.D.B.), and Michigan State University, East Lansing (D.R.N.) - all in Michigan; the Departments of Epidemiology and Medicine, College of Public Health, University of Iowa, Iowa City (J.G.R.); the Department of Pharmacological and Biomolecular Sciences, University of Milan and MultiMedica Istituto di Ricovero e Cura a Carattere Scientifico, Milan (A.L.C.); INSERM, Pitié-Salpêtrière University Hospital, Paris (M.J.C.); the Global Genomics Group, Richmond, VA (S.V.); the Thrombolysis in Myocardial Infarction Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston (R.P.G., M.S.S.); the Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom (G.D.S.); and the Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health and Science University, Portland (S.F.).
authors.forename: Marc S
authors.initials: MS
authors.lastname: Sabatine
mesh_terms: D002318:Cardiovascular Diseases / Q000235:genetics*; D008078:Cholesterol, LDL / Q000097:blood*; D003920:Diabetes Mellitus / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D000071449:Proprotein Convertase 9 / Q000235:genetics*; D011897:Random Allocation; D012306:Risk
chemical_list: D008078:Cholesterol, LDL; C553220:HMGCR protein, human; D006903:Hydroxymethylglutaryl CoA Reductases; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9