title: Polygenic Risk Score Identifies Subgroup With Higher Burden of Atherosclerosis and Greater Relative Benefit From Statin Therapy in the Primary Prevention Setting.
abstract: BACKGROUND
  Relative risk reduction with statin therapy has been consistent across nearly all subgroups studied to date. However, in analyses of 2 randomized controlled primary prevention trials (ASCOT [Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm] and JUPITER [Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin]), statin therapy led to a greater relative risk reduction among a subgroup at high genetic risk. Here, we aimed to confirm this observation in a third primary prevention randomized controlled trial. In addition, we assessed whether those at high genetic risk had a greater burden of subclinical coronary atherosclerosis.
  
  
  METHODS
  We studied participants from a randomized controlled trial of primary prevention with statin therapy (WOSCOPS [West of Scotland Coronary Prevention Study]; n=4910) and 2 observational cohort studies (CARDIA [Coronary Artery Risk Development in Young Adults] and BioImage; n=1154 and 4392, respectively). For each participant, we calculated a polygenic risk score derived from up to 57 common DNA sequence variants previously associated with coronary heart disease. We compared the relative efficacy of statin therapy in those at high genetic risk (top quintile of polygenic risk score) versus all others (WOSCOPS), as well as the association between the polygenic risk score and coronary artery calcification (CARDIA) and carotid artery plaque burden (BioImage).
  
  
  RESULTS
  Among WOSCOPS trial participants at high genetic risk, statin therapy was associated with a relative risk reduction of 44% (95% confidence interval [CI], 22-60;P<0.001), whereas in all others, the relative risk reduction was 24% (95% CI, 8-37;P=0.004) despite similar low-density lipoprotein cholesterol lowering. In a study-level meta-analysis across the WOSCOPS, ASCOT, and JUPITER primary prevention, relative risk reduction in those at high genetic risk was 46% versus 26% in all others (Pfor heterogeneity=0.05). Across all 3 studies, the absolute risk reduction with statin therapy was 3.6% (95% CI, 2.0-5.1) among those in the high genetic risk group and 1.3% (95% CI, 0.6-1.9) in all others. Each 1-SD increase in the polygenic risk score was associated with 1.32-fold (95% CI, 1.04-1.68) greater likelihood of having coronary artery calcification and 9.7% higher (95% CI, 2.2-17.8) burden of carotid plaque.
  
  
  CONCLUSIONS
  Those at high genetic risk have a greater burden of subclinical atherosclerosis and derive greater relative and absolute benefit from statin therapy to prevent a first coronary heart disease event.
  
  
  BACKGROUND
  URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00738725 (BioImage) and NCT00005130 (CARDIA). WOSCOPS was carried out and completed before the requirement for clinical trial registration.
authors.affiliation: From Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Boston (P.N., S.K.); Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge (P.N., S.K.); Department of Medicine, Harvard Medical School, Boston, MA (P.N., S.K.); Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, United Kingdom (R.Y., A.B.); Division of Statistical Genetics, Department of Genetics, Cardiovascular Division, Department of Medicine, and McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO (N.O.S.); British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences (S.P., N.S.), and Robertson Centre for Biostatistics (I.F.), University of Glasgow, United Kingdom; Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, United Kingdom (S.P.); Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY (U.B., R.M., S.S., V.F.); Genetics and Pharmacogenomics Department, Merck Sharpe & Dohme Corp, Boston, MA (D.F.R.); and Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (D.J.R.).
authors.forename: Pradeep
authors.initials: P
authors.lastname: Natarajan
authors.affiliation: From Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Boston (P.N., S.K.); Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge (P.N., S.K.); Department of Medicine, Harvard Medical School, Boston, MA (P.N., S.K.); Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, United Kingdom (R.Y., A.B.); Division of Statistical Genetics, Department of Genetics, Cardiovascular Division, Department of Medicine, and McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO (N.O.S.); British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences (S.P., N.S.), and Robertson Centre for Biostatistics (I.F.), University of Glasgow, United Kingdom; Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, United Kingdom (S.P.); Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY (U.B., R.M., S.S., V.F.); Genetics and Pharmacogenomics Department, Merck Sharpe & Dohme Corp, Boston, MA (D.F.R.); and Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (D.J.R.).
authors.forename: Robin
authors.initials: R
authors.lastname: Young
authors.affiliation: From Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Boston (P.N., S.K.); Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge (P.N., S.K.); Department of Medicine, Harvard Medical School, Boston, MA (P.N., S.K.); Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, United Kingdom (R.Y., A.B.); Division of Statistical Genetics, Department of Genetics, Cardiovascular Division, Department of Medicine, and McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO (N.O.S.); British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences (S.P., N.S.), and Robertson Centre for Biostatistics (I.F.), University of Glasgow, United Kingdom; Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, United Kingdom (S.P.); Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY (U.B., R.M., S.S., V.F.); Genetics and Pharmacogenomics Department, Merck Sharpe & Dohme Corp, Boston, MA (D.F.R.); and Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (D.J.R.).
authors.forename: Nathan O
authors.initials: NO
authors.lastname: Stitziel
authors.affiliation: From Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Boston (P.N., S.K.); Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge (P.N., S.K.); Department of Medicine, Harvard Medical School, Boston, MA (P.N., S.K.); Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, United Kingdom (R.Y., A.B.); Division of Statistical Genetics, Department of Genetics, Cardiovascular Division, Department of Medicine, and McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO (N.O.S.); British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences (S.P., N.S.), and Robertson Centre for Biostatistics (I.F.), University of Glasgow, United Kingdom; Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, United Kingdom (S.P.); Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY (U.B., R.M., S.S., V.F.); Genetics and Pharmacogenomics Department, Merck Sharpe & Dohme Corp, Boston, MA (D.F.R.); and Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (D.J.R.).
authors.forename: Sandosh
authors.initials: S
authors.lastname: Padmanabhan
authors.affiliation: From Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Boston (P.N., S.K.); Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge (P.N., S.K.); Department of Medicine, Harvard Medical School, Boston, MA (P.N., S.K.); Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, United Kingdom (R.Y., A.B.); Division of Statistical Genetics, Department of Genetics, Cardiovascular Division, Department of Medicine, and McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO (N.O.S.); British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences (S.P., N.S.), and Robertson Centre for Biostatistics (I.F.), University of Glasgow, United Kingdom; Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, United Kingdom (S.P.); Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY (U.B., R.M., S.S., V.F.); Genetics and Pharmacogenomics Department, Merck Sharpe & Dohme Corp, Boston, MA (D.F.R.); and Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (D.J.R.).
authors.forename: Usman
authors.initials: U
authors.lastname: Baber
authors.affiliation: From Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Boston (P.N., S.K.); Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge (P.N., S.K.); Department of Medicine, Harvard Medical School, Boston, MA (P.N., S.K.); Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, United Kingdom (R.Y., A.B.); Division of Statistical Genetics, Department of Genetics, Cardiovascular Division, Department of Medicine, and McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO (N.O.S.); British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences (S.P., N.S.), and Robertson Centre for Biostatistics (I.F.), University of Glasgow, United Kingdom; Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, United Kingdom (S.P.); Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY (U.B., R.M., S.S., V.F.); Genetics and Pharmacogenomics Department, Merck Sharpe & Dohme Corp, Boston, MA (D.F.R.); and Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (D.J.R.).
authors.forename: Roxana
authors.initials: R
authors.lastname: Mehran
authors.affiliation: From Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Boston (P.N., S.K.); Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge (P.N., S.K.); Department of Medicine, Harvard Medical School, Boston, MA (P.N., S.K.); Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, United Kingdom (R.Y., A.B.); Division of Statistical Genetics, Department of Genetics, Cardiovascular Division, Department of Medicine, and McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO (N.O.S.); British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences (S.P., N.S.), and Robertson Centre for Biostatistics (I.F.), University of Glasgow, United Kingdom; Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, United Kingdom (S.P.); Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY (U.B., R.M., S.S., V.F.); Genetics and Pharmacogenomics Department, Merck Sharpe & Dohme Corp, Boston, MA (D.F.R.); and Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (D.J.R.).
authors.forename: Samantha
authors.initials: S
authors.lastname: Sartori
authors.affiliation: From Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Boston (P.N., S.K.); Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge (P.N., S.K.); Department of Medicine, Harvard Medical School, Boston, MA (P.N., S.K.); Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, United Kingdom (R.Y., A.B.); Division of Statistical Genetics, Department of Genetics, Cardiovascular Division, Department of Medicine, and McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO (N.O.S.); British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences (S.P., N.S.), and Robertson Centre for Biostatistics (I.F.), University of Glasgow, United Kingdom; Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, United Kingdom (S.P.); Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY (U.B., R.M., S.S., V.F.); Genetics and Pharmacogenomics Department, Merck Sharpe & Dohme Corp, Boston, MA (D.F.R.); and Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (D.J.R.).
authors.forename: Valentin
authors.initials: V
authors.lastname: Fuster
authors.affiliation: From Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Boston (P.N., S.K.); Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge (P.N., S.K.); Department of Medicine, Harvard Medical School, Boston, MA (P.N., S.K.); Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, United Kingdom (R.Y., A.B.); Division of Statistical Genetics, Department of Genetics, Cardiovascular Division, Department of Medicine, and McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO (N.O.S.); British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences (S.P., N.S.), and Robertson Centre for Biostatistics (I.F.), University of Glasgow, United Kingdom; Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, United Kingdom (S.P.); Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY (U.B., R.M., S.S., V.F.); Genetics and Pharmacogenomics Department, Merck Sharpe & Dohme Corp, Boston, MA (D.F.R.); and Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (D.J.R.).
authors.forename: Dermot F
authors.initials: DF
authors.lastname: Reilly
authors.affiliation: From Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Boston (P.N., S.K.); Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge (P.N., S.K.); Department of Medicine, Harvard Medical School, Boston, MA (P.N., S.K.); Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, United Kingdom (R.Y., A.B.); Division of Statistical Genetics, Department of Genetics, Cardiovascular Division, Department of Medicine, and McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO (N.O.S.); British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences (S.P., N.S.), and Robertson Centre for Biostatistics (I.F.), University of Glasgow, United Kingdom; Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, United Kingdom (S.P.); Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY (U.B., R.M., S.S., V.F.); Genetics and Pharmacogenomics Department, Merck Sharpe & Dohme Corp, Boston, MA (D.F.R.); and Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (D.J.R.).
authors.forename: Adam
authors.initials: A
authors.lastname: Butterworth
authors.affiliation: From Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Boston (P.N., S.K.); Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge (P.N., S.K.); Department of Medicine, Harvard Medical School, Boston, MA (P.N., S.K.); Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, United Kingdom (R.Y., A.B.); Division of Statistical Genetics, Department of Genetics, Cardiovascular Division, Department of Medicine, and McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO (N.O.S.); British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences (S.P., N.S.), and Robertson Centre for Biostatistics (I.F.), University of Glasgow, United Kingdom; Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, United Kingdom (S.P.); Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY (U.B., R.M., S.S., V.F.); Genetics and Pharmacogenomics Department, Merck Sharpe & Dohme Corp, Boston, MA (D.F.R.); and Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (D.J.R.).
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
authors.affiliation: From Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Boston (P.N., S.K.); Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge (P.N., S.K.); Department of Medicine, Harvard Medical School, Boston, MA (P.N., S.K.); Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, United Kingdom (R.Y., A.B.); Division of Statistical Genetics, Department of Genetics, Cardiovascular Division, Department of Medicine, and McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO (N.O.S.); British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences (S.P., N.S.), and Robertson Centre for Biostatistics (I.F.), University of Glasgow, United Kingdom; Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, United Kingdom (S.P.); Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY (U.B., R.M., S.S., V.F.); Genetics and Pharmacogenomics Department, Merck Sharpe & Dohme Corp, Boston, MA (D.F.R.); and Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (D.J.R.).
authors.forename: Ian
authors.initials: I
authors.lastname: Ford
authors.affiliation: From Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Boston (P.N., S.K.); Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge (P.N., S.K.); Department of Medicine, Harvard Medical School, Boston, MA (P.N., S.K.); Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, United Kingdom (R.Y., A.B.); Division of Statistical Genetics, Department of Genetics, Cardiovascular Division, Department of Medicine, and McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO (N.O.S.); British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences (S.P., N.S.), and Robertson Centre for Biostatistics (I.F.), University of Glasgow, United Kingdom; Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, United Kingdom (S.P.); Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY (U.B., R.M., S.S., V.F.); Genetics and Pharmacogenomics Department, Merck Sharpe & Dohme Corp, Boston, MA (D.F.R.); and Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (D.J.R.).
authors.forename: Naveed
authors.initials: N
authors.lastname: Sattar
authors.affiliation: From Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Boston (P.N., S.K.); Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge (P.N., S.K.); Department of Medicine, Harvard Medical School, Boston, MA (P.N., S.K.); Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, United Kingdom (R.Y., A.B.); Division of Statistical Genetics, Department of Genetics, Cardiovascular Division, Department of Medicine, and McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO (N.O.S.); British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences (S.P., N.S.), and Robertson Centre for Biostatistics (I.F.), University of Glasgow, United Kingdom; Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, United Kingdom (S.P.); Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY (U.B., R.M., S.S., V.F.); Genetics and Pharmacogenomics Department, Merck Sharpe & Dohme Corp, Boston, MA (D.F.R.); and Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (D.J.R.). skathiresan1@mgh.harvard.edu.
authors.forename: Sekar
authors.initials: S
authors.lastname: Kathiresan
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D055815:Young Adult; D050197:Atherosclerosis / Q000175:diagnosis / Q000235:genetics / Q000517:prevention & control; D015331:Cohort Studies; D017281:Cost of Illness; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D020412:Multifactorial Inheritance / Q000235:genetics; D011322:Primary Prevention / Q000379:methods; D012307:Risk Factors; D064887:Observational Studies as Topic; D016032:Randomized Controlled Trials as Topic
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors
keywords: humans; hydroxymethylglutaryl-CoA reductase inhibitors; polymorphism, genetic; primary prevention; vascular calcification