title: Serum lipid levels, body mass index, and their role in coronary artery calcification: a polygenic analysis.
abstract: BACKGROUND
  Coronary artery calcification (CAC) is widely regarded as a cumulative lifetime measure of atherosclerosis, but it remains unclear what is the relationship between calcification and traditional risk factors for coronary artery disease (CAD) and myocardial infarction (MI). This study characterizes the genetic architecture of CAC by evaluating the overall impact of common alleles associated with CAD/MI and its traditional risk factors.
  
  
  RESULTS
  On the basis of summary-association results from the CARDIoGRAMplusC4D study of CAD/MI, we calculated polygenic risk scores in 2599 participants of the Dutch and Belgian Lung Cancer Screening (NELSON) trial, in whom quantitative CAC levels (Agatston scores) were determined from chest computerized tomographic imaging data. The most significant polygenic model explained ≈14% of the observed CAC variance (P=1.6×10(-11)), which points to a residual effect because of many as yet unknown loci that overlap between CAD/MI and CAC. In addition, we constructed risk scores based on published single-nucleotide polymorphism associations for traditional cardiovascular risk factors and tested these scores for association with CAC. We found nominally significant associations for genetic risk scores of low-density lipoprotein-cholesterol, total cholesterol, and body mass index, which were successfully replicated in 2182 individuals of the Heinz Nixdorf Recall Study.
  
  
  CONCLUSIONS
  Pervasive polygenic sharing between CAC and CAD/MI suggests that a substantial fraction of the heritable risk for CAD/MI is mediated through arterial calcification. We also provide evidence that genetic variants associated with serum lipid levels and body mass index influence CAC levels.
authors.affiliation: From the Department of Medical Genetics, Center for Molecular Medicine (J.v.S., P.I.W.d.B.), Image Sciences Institute (I.I., M.A.V.), Department of Cardiology (V.T.); Department of Radiology (P.A.d.J.), Department of Epidemiology, Julius Center for Health Sciences and Primary Care (P.I.W.d.B.), University Medical Center Utrecht, Utrecht, The Netherlands; Institute for Medical Informatics, Biometry and Epidemiology (S.P., S.M.), Clinic of Cardiology, West-German Heart Centre (R.E.), University Hospital Essen, Essen, Germany; Department of Genetics (J.S., M.P.), Department of Epidemiology (J.S.), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Institute of Human Genetics (P.F., M.M.N.), Department of Genomics, Life and Brain Center (P.F., M.M.N.), University of Bonn, Bonn, Germany; Division of Medical Genetics, University Hospital and Department of Biomedicine, University of Basel, Basel, Switzerland (P.F.); Department of Radiology-Radiodiagnostics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands (M.O.); and Department of Public Health, Erasmus Medical Center, Rotterdam, The Netherlands (H.J.d.K.).
authors.forename: Jessica
authors.initials: J
authors.lastname: van Setten
authors.affiliation: From the Department of Medical Genetics, Center for Molecular Medicine (J.v.S., P.I.W.d.B.), Image Sciences Institute (I.I., M.A.V.), Department of Cardiology (V.T.); Department of Radiology (P.A.d.J.), Department of Epidemiology, Julius Center for Health Sciences and Primary Care (P.I.W.d.B.), University Medical Center Utrecht, Utrecht, The Netherlands; Institute for Medical Informatics, Biometry and Epidemiology (S.P., S.M.), Clinic of Cardiology, West-German Heart Centre (R.E.), University Hospital Essen, Essen, Germany; Department of Genetics (J.S., M.P.), Department of Epidemiology (J.S.), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Institute of Human Genetics (P.F., M.M.N.), Department of Genomics, Life and Brain Center (P.F., M.M.N.), University of Bonn, Bonn, Germany; Division of Medical Genetics, University Hospital and Department of Biomedicine, University of Basel, Basel, Switzerland (P.F.); Department of Radiology-Radiodiagnostics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands (M.O.); and Department of Public Health, Erasmus Medical Center, Rotterdam, The Netherlands (H.J.d.K.).
authors.forename: Ivana
authors.initials: I
authors.lastname: Išgum
authors.affiliation: From the Department of Medical Genetics, Center for Molecular Medicine (J.v.S., P.I.W.d.B.), Image Sciences Institute (I.I., M.A.V.), Department of Cardiology (V.T.); Department of Radiology (P.A.d.J.), Department of Epidemiology, Julius Center for Health Sciences and Primary Care (P.I.W.d.B.), University Medical Center Utrecht, Utrecht, The Netherlands; Institute for Medical Informatics, Biometry and Epidemiology (S.P., S.M.), Clinic of Cardiology, West-German Heart Centre (R.E.), University Hospital Essen, Essen, Germany; Department of Genetics (J.S., M.P.), Department of Epidemiology (J.S.), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Institute of Human Genetics (P.F., M.M.N.), Department of Genomics, Life and Brain Center (P.F., M.M.N.), University of Bonn, Bonn, Germany; Division of Medical Genetics, University Hospital and Department of Biomedicine, University of Basel, Basel, Switzerland (P.F.); Department of Radiology-Radiodiagnostics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands (M.O.); and Department of Public Health, Erasmus Medical Center, Rotterdam, The Netherlands (H.J.d.K.).
authors.forename: Sonali
authors.initials: S
authors.lastname: Pechlivanis
authors.affiliation: From the Department of Medical Genetics, Center for Molecular Medicine (J.v.S., P.I.W.d.B.), Image Sciences Institute (I.I., M.A.V.), Department of Cardiology (V.T.); Department of Radiology (P.A.d.J.), Department of Epidemiology, Julius Center for Health Sciences and Primary Care (P.I.W.d.B.), University Medical Center Utrecht, Utrecht, The Netherlands; Institute for Medical Informatics, Biometry and Epidemiology (S.P., S.M.), Clinic of Cardiology, West-German Heart Centre (R.E.), University Hospital Essen, Essen, Germany; Department of Genetics (J.S., M.P.), Department of Epidemiology (J.S.), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Institute of Human Genetics (P.F., M.M.N.), Department of Genomics, Life and Brain Center (P.F., M.M.N.), University of Bonn, Bonn, Germany; Division of Medical Genetics, University Hospital and Department of Biomedicine, University of Basel, Basel, Switzerland (P.F.); Department of Radiology-Radiodiagnostics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands (M.O.); and Department of Public Health, Erasmus Medical Center, Rotterdam, The Netherlands (H.J.d.K.).
authors.forename: Vinicius
authors.initials: V
authors.lastname: Tragante
authors.affiliation: From the Department of Medical Genetics, Center for Molecular Medicine (J.v.S., P.I.W.d.B.), Image Sciences Institute (I.I., M.A.V.), Department of Cardiology (V.T.); Department of Radiology (P.A.d.J.), Department of Epidemiology, Julius Center for Health Sciences and Primary Care (P.I.W.d.B.), University Medical Center Utrecht, Utrecht, The Netherlands; Institute for Medical Informatics, Biometry and Epidemiology (S.P., S.M.), Clinic of Cardiology, West-German Heart Centre (R.E.), University Hospital Essen, Essen, Germany; Department of Genetics (J.S., M.P.), Department of Epidemiology (J.S.), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Institute of Human Genetics (P.F., M.M.N.), Department of Genomics, Life and Brain Center (P.F., M.M.N.), University of Bonn, Bonn, Germany; Division of Medical Genetics, University Hospital and Department of Biomedicine, University of Basel, Basel, Switzerland (P.F.); Department of Radiology-Radiodiagnostics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands (M.O.); and Department of Public Health, Erasmus Medical Center, Rotterdam, The Netherlands (H.J.d.K.).
authors.forename: Pim A
authors.initials: PA
authors.lastname: de Jong
authors.affiliation: From the Department of Medical Genetics, Center for Molecular Medicine (J.v.S., P.I.W.d.B.), Image Sciences Institute (I.I., M.A.V.), Department of Cardiology (V.T.); Department of Radiology (P.A.d.J.), Department of Epidemiology, Julius Center for Health Sciences and Primary Care (P.I.W.d.B.), University Medical Center Utrecht, Utrecht, The Netherlands; Institute for Medical Informatics, Biometry and Epidemiology (S.P., S.M.), Clinic of Cardiology, West-German Heart Centre (R.E.), University Hospital Essen, Essen, Germany; Department of Genetics (J.S., M.P.), Department of Epidemiology (J.S.), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Institute of Human Genetics (P.F., M.M.N.), Department of Genomics, Life and Brain Center (P.F., M.M.N.), University of Bonn, Bonn, Germany; Division of Medical Genetics, University Hospital and Department of Biomedicine, University of Basel, Basel, Switzerland (P.F.); Department of Radiology-Radiodiagnostics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands (M.O.); and Department of Public Health, Erasmus Medical Center, Rotterdam, The Netherlands (H.J.d.K.).
authors.forename: Joanna
authors.initials: J
authors.lastname: Smolonska
authors.affiliation: From the Department of Medical Genetics, Center for Molecular Medicine (J.v.S., P.I.W.d.B.), Image Sciences Institute (I.I., M.A.V.), Department of Cardiology (V.T.); Department of Radiology (P.A.d.J.), Department of Epidemiology, Julius Center for Health Sciences and Primary Care (P.I.W.d.B.), University Medical Center Utrecht, Utrecht, The Netherlands; Institute for Medical Informatics, Biometry and Epidemiology (S.P., S.M.), Clinic of Cardiology, West-German Heart Centre (R.E.), University Hospital Essen, Essen, Germany; Department of Genetics (J.S., M.P.), Department of Epidemiology (J.S.), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Institute of Human Genetics (P.F., M.M.N.), Department of Genomics, Life and Brain Center (P.F., M.M.N.), University of Bonn, Bonn, Germany; Division of Medical Genetics, University Hospital and Department of Biomedicine, University of Basel, Basel, Switzerland (P.F.); Department of Radiology-Radiodiagnostics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands (M.O.); and Department of Public Health, Erasmus Medical Center, Rotterdam, The Netherlands (H.J.d.K.).
authors.forename: Mathieu
authors.initials: M
authors.lastname: Platteel
authors.affiliation: From the Department of Medical Genetics, Center for Molecular Medicine (J.v.S., P.I.W.d.B.), Image Sciences Institute (I.I., M.A.V.), Department of Cardiology (V.T.); Department of Radiology (P.A.d.J.), Department of Epidemiology, Julius Center for Health Sciences and Primary Care (P.I.W.d.B.), University Medical Center Utrecht, Utrecht, The Netherlands; Institute for Medical Informatics, Biometry and Epidemiology (S.P., S.M.), Clinic of Cardiology, West-German Heart Centre (R.E.), University Hospital Essen, Essen, Germany; Department of Genetics (J.S., M.P.), Department of Epidemiology (J.S.), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Institute of Human Genetics (P.F., M.M.N.), Department of Genomics, Life and Brain Center (P.F., M.M.N.), University of Bonn, Bonn, Germany; Division of Medical Genetics, University Hospital and Department of Biomedicine, University of Basel, Basel, Switzerland (P.F.); Department of Radiology-Radiodiagnostics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands (M.O.); and Department of Public Health, Erasmus Medical Center, Rotterdam, The Netherlands (H.J.d.K.).
authors.forename: Per
authors.initials: P
authors.lastname: Hoffmann
authors.affiliation: From the Department of Medical Genetics, Center for Molecular Medicine (J.v.S., P.I.W.d.B.), Image Sciences Institute (I.I., M.A.V.), Department of Cardiology (V.T.); Department of Radiology (P.A.d.J.), Department of Epidemiology, Julius Center for Health Sciences and Primary Care (P.I.W.d.B.), University Medical Center Utrecht, Utrecht, The Netherlands; Institute for Medical Informatics, Biometry and Epidemiology (S.P., S.M.), Clinic of Cardiology, West-German Heart Centre (R.E.), University Hospital Essen, Essen, Germany; Department of Genetics (J.S., M.P.), Department of Epidemiology (J.S.), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Institute of Human Genetics (P.F., M.M.N.), Department of Genomics, Life and Brain Center (P.F., M.M.N.), University of Bonn, Bonn, Germany; Division of Medical Genetics, University Hospital and Department of Biomedicine, University of Basel, Basel, Switzerland (P.F.); Department of Radiology-Radiodiagnostics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands (M.O.); and Department of Public Health, Erasmus Medical Center, Rotterdam, The Netherlands (H.J.d.K.).
authors.forename: Matthijs
authors.initials: M
authors.lastname: Oudkerk
authors.affiliation: From the Department of Medical Genetics, Center for Molecular Medicine (J.v.S., P.I.W.d.B.), Image Sciences Institute (I.I., M.A.V.), Department of Cardiology (V.T.); Department of Radiology (P.A.d.J.), Department of Epidemiology, Julius Center for Health Sciences and Primary Care (P.I.W.d.B.), University Medical Center Utrecht, Utrecht, The Netherlands; Institute for Medical Informatics, Biometry and Epidemiology (S.P., S.M.), Clinic of Cardiology, West-German Heart Centre (R.E.), University Hospital Essen, Essen, Germany; Department of Genetics (J.S., M.P.), Department of Epidemiology (J.S.), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Institute of Human Genetics (P.F., M.M.N.), Department of Genomics, Life and Brain Center (P.F., M.M.N.), University of Bonn, Bonn, Germany; Division of Medical Genetics, University Hospital and Department of Biomedicine, University of Basel, Basel, Switzerland (P.F.); Department of Radiology-Radiodiagnostics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands (M.O.); and Department of Public Health, Erasmus Medical Center, Rotterdam, The Netherlands (H.J.d.K.).
authors.forename: Harry J
authors.initials: HJ
authors.lastname: de Koning
authors.affiliation: From the Department of Medical Genetics, Center for Molecular Medicine (J.v.S., P.I.W.d.B.), Image Sciences Institute (I.I., M.A.V.), Department of Cardiology (V.T.); Department of Radiology (P.A.d.J.), Department of Epidemiology, Julius Center for Health Sciences and Primary Care (P.I.W.d.B.), University Medical Center Utrecht, Utrecht, The Netherlands; Institute for Medical Informatics, Biometry and Epidemiology (S.P., S.M.), Clinic of Cardiology, West-German Heart Centre (R.E.), University Hospital Essen, Essen, Germany; Department of Genetics (J.S., M.P.), Department of Epidemiology (J.S.), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Institute of Human Genetics (P.F., M.M.N.), Department of Genomics, Life and Brain Center (P.F., M.M.N.), University of Bonn, Bonn, Germany; Division of Medical Genetics, University Hospital and Department of Biomedicine, University of Basel, Basel, Switzerland (P.F.); Department of Radiology-Radiodiagnostics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands (M.O.); and Department of Public Health, Erasmus Medical Center, Rotterdam, The Netherlands (H.J.d.K.).
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: From the Department of Medical Genetics, Center for Molecular Medicine (J.v.S., P.I.W.d.B.), Image Sciences Institute (I.I., M.A.V.), Department of Cardiology (V.T.); Department of Radiology (P.A.d.J.), Department of Epidemiology, Julius Center for Health Sciences and Primary Care (P.I.W.d.B.), University Medical Center Utrecht, Utrecht, The Netherlands; Institute for Medical Informatics, Biometry and Epidemiology (S.P., S.M.), Clinic of Cardiology, West-German Heart Centre (R.E.), University Hospital Essen, Essen, Germany; Department of Genetics (J.S., M.P.), Department of Epidemiology (J.S.), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Institute of Human Genetics (P.F., M.M.N.), Department of Genomics, Life and Brain Center (P.F., M.M.N.), University of Bonn, Bonn, Germany; Division of Medical Genetics, University Hospital and Department of Biomedicine, University of Basel, Basel, Switzerland (P.F.); Department of Radiology-Radiodiagnostics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands (M.O.); and Department of Public Health, Erasmus Medical Center, Rotterdam, The Netherlands (H.J.d.K.).
authors.forename: Susanne
authors.initials: S
authors.lastname: Moebus
authors.affiliation: From the Department of Medical Genetics, Center for Molecular Medicine (J.v.S., P.I.W.d.B.), Image Sciences Institute (I.I., M.A.V.), Department of Cardiology (V.T.); Department of Radiology (P.A.d.J.), Department of Epidemiology, Julius Center for Health Sciences and Primary Care (P.I.W.d.B.), University Medical Center Utrecht, Utrecht, The Netherlands; Institute for Medical Informatics, Biometry and Epidemiology (S.P., S.M.), Clinic of Cardiology, West-German Heart Centre (R.E.), University Hospital Essen, Essen, Germany; Department of Genetics (J.S., M.P.), Department of Epidemiology (J.S.), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Institute of Human Genetics (P.F., M.M.N.), Department of Genomics, Life and Brain Center (P.F., M.M.N.), University of Bonn, Bonn, Germany; Division of Medical Genetics, University Hospital and Department of Biomedicine, University of Basel, Basel, Switzerland (P.F.); Department of Radiology-Radiodiagnostics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands (M.O.); and Department of Public Health, Erasmus Medical Center, Rotterdam, The Netherlands (H.J.d.K.).
authors.forename: Raimund
authors.initials: R
authors.lastname: Erbel
authors.affiliation: From the Department of Medical Genetics, Center for Molecular Medicine (J.v.S., P.I.W.d.B.), Image Sciences Institute (I.I., M.A.V.), Department of Cardiology (V.T.); Department of Radiology (P.A.d.J.), Department of Epidemiology, Julius Center for Health Sciences and Primary Care (P.I.W.d.B.), University Medical Center Utrecht, Utrecht, The Netherlands; Institute for Medical Informatics, Biometry and Epidemiology (S.P., S.M.), Clinic of Cardiology, West-German Heart Centre (R.E.), University Hospital Essen, Essen, Germany; Department of Genetics (J.S., M.P.), Department of Epidemiology (J.S.), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Institute of Human Genetics (P.F., M.M.N.), Department of Genomics, Life and Brain Center (P.F., M.M.N.), University of Bonn, Bonn, Germany; Division of Medical Genetics, University Hospital and Department of Biomedicine, University of Basel, Basel, Switzerland (P.F.); Department of Radiology-Radiodiagnostics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands (M.O.); and Department of Public Health, Erasmus Medical Center, Rotterdam, The Netherlands (H.J.d.K.).
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Jöckel
authors.affiliation: From the Department of Medical Genetics, Center for Molecular Medicine (J.v.S., P.I.W.d.B.), Image Sciences Institute (I.I., M.A.V.), Department of Cardiology (V.T.); Department of Radiology (P.A.d.J.), Department of Epidemiology, Julius Center for Health Sciences and Primary Care (P.I.W.d.B.), University Medical Center Utrecht, Utrecht, The Netherlands; Institute for Medical Informatics, Biometry and Epidemiology (S.P., S.M.), Clinic of Cardiology, West-German Heart Centre (R.E.), University Hospital Essen, Essen, Germany; Department of Genetics (J.S., M.P.), Department of Epidemiology (J.S.), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Institute of Human Genetics (P.F., M.M.N.), Department of Genomics, Life and Brain Center (P.F., M.M.N.), University of Bonn, Bonn, Germany; Division of Medical Genetics, University Hospital and Department of Biomedicine, University of Basel, Basel, Switzerland (P.F.); Department of Radiology-Radiodiagnostics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands (M.O.); and Department of Public Health, Erasmus Medical Center, Rotterdam, The Netherlands (H.J.d.K.).
authors.forename: Max A
authors.initials: MA
authors.lastname: Viergever
authors.affiliation: From the Department of Medical Genetics, Center for Molecular Medicine (J.v.S., P.I.W.d.B.), Image Sciences Institute (I.I., M.A.V.), Department of Cardiology (V.T.); Department of Radiology (P.A.d.J.), Department of Epidemiology, Julius Center for Health Sciences and Primary Care (P.I.W.d.B.), University Medical Center Utrecht, Utrecht, The Netherlands; Institute for Medical Informatics, Biometry and Epidemiology (S.P., S.M.), Clinic of Cardiology, West-German Heart Centre (R.E.), University Hospital Essen, Essen, Germany; Department of Genetics (J.S., M.P.), Department of Epidemiology (J.S.), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Institute of Human Genetics (P.F., M.M.N.), Department of Genomics, Life and Brain Center (P.F., M.M.N.), University of Bonn, Bonn, Germany; Division of Medical Genetics, University Hospital and Department of Biomedicine, University of Basel, Basel, Switzerland (P.F.); Department of Radiology-Radiodiagnostics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands (M.O.); and Department of Public Health, Erasmus Medical Center, Rotterdam, The Netherlands (H.J.d.K.).
authors.forename: Willem P Th M
authors.initials: WP
authors.lastname: Mali
authors.affiliation: From the Department of Medical Genetics, Center for Molecular Medicine (J.v.S., P.I.W.d.B.), Image Sciences Institute (I.I., M.A.V.), Department of Cardiology (V.T.); Department of Radiology (P.A.d.J.), Department of Epidemiology, Julius Center for Health Sciences and Primary Care (P.I.W.d.B.), University Medical Center Utrecht, Utrecht, The Netherlands; Institute for Medical Informatics, Biometry and Epidemiology (S.P., S.M.), Clinic of Cardiology, West-German Heart Centre (R.E.), University Hospital Essen, Essen, Germany; Department of Genetics (J.S., M.P.), Department of Epidemiology (J.S.), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Institute of Human Genetics (P.F., M.M.N.), Department of Genomics, Life and Brain Center (P.F., M.M.N.), University of Bonn, Bonn, Germany; Division of Medical Genetics, University Hospital and Department of Biomedicine, University of Basel, Basel, Switzerland (P.F.); Department of Radiology-Radiodiagnostics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands (M.O.); and Department of Public Health, Erasmus Medical Center, Rotterdam, The Netherlands (H.J.d.K.). pdebakker@umcutrecht.nl.
authors.forename: Paul I W
authors.initials: PI
authors.lastname: de Bakker
mesh_terms: D001530:Belgium; D015992:Body Mass Index; D003324:Coronary Artery Disease / Q000097:blood / Q000235:genetics; D005260:Female; D006801:Humans; D008055:Lipids / Q000097:blood*; D008297:Male; D020412:Multifactorial Inheritance; D009426:Netherlands; D061205:Vascular Calcification / Q000097:blood / Q000235:genetics
chemical_list: D008055:Lipids
keywords: coronary artery disease; genome-wide association study; myocardial infarction