Rare Protein-Truncating Variants in <i>APOB</i> , Lower Low-Density Lipoprotein Cholesterol, and Protection Against Coronary Heart Disease

  • Gina M. Peloso
    Department of Biostatistics, Boston University School of Public Health, MA (G.M.P.).
  • Akihiro Nomura
    Department of Cardiovascular and Internal Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, Japan (A. Nomura, A. Nohara, M.K., H.T.).
  • Amit V. Khera
    Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (A.V.K., M.C., S.K.).
  • Mark Chaffin
    Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (A.V.K., M.C., S.K.).
  • Hong-Hee Won
    Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Samsung Medical Center, Seoul, Republic of Korea (H.-H.W.).
  • Diego Ardissino
    Cardiology, Azienda Ospedaliero-Universitaria di Parma, University of Parma, Parma, Italy (D.A.).
  • John Danesh
    MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care (J.D.), University of Cambridge, Cambridge, United Kingdom.
  • Heribert Schunkert
    Deutsches Herzzentrum München, Technische Universität München, Deutsches Zentrum für Herz-Kreislauf-Forschung, München, Germany (H.S.).
  • James G. Wilson
    Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS (J.G.W.).
  • Nilesh Samani
    Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom (N.S.).
  • Jeanette Erdmann
    Institute for Integrative and Experimental Genomics, University of Lübeck, Germany (J.E.).
  • Ruth McPherson
    University of Ottawa Heart Institute, Ottawa, Canada (R.M.).
  • Hugh Watkins
    Cardiovascular Medicine, Radcliffe Department of Medicine and Wellcome Trust Center for Human Genetics, University of Oxford, Oxford, United Kingdom (H.W.).
  • Danish Saleheen
    Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (D.S.).
  • Shane McCarthy
    Regeneron Genetics Center, Tarrytown, NY (S.M., T.M.T., F.E.D., A.B.).
  • Tanya M. Teslovich
    Regeneron Genetics Center, Tarrytown, NY (S.M., T.M.T., F.E.D., A.B.).
  • Joseph B. Leader
    Geisinger Health System, Danville, PA (J.B.L., H.L.K., D.J.C.).
  • H. Lester Kirchner
    Geisinger Health System, Danville, PA (J.B.L., H.L.K., D.J.C.).
  • Jaume Marrugat
    Registre Gironí del Cor group, IMIM (Hospital del Mar Research Institute), Barcelona, Spain (J.M.). CIBER Enfermedades Cardiovasculares (CIBERCV), Barcelona, Spain (J.M.).
  • Atsushi Nohara
    Department of Cardiovascular and Internal Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, Japan (A. Nomura, A. Nohara, M.K., H.T.).
  • Masa-aki Kawashiri
    Department of Cardiovascular and Internal Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, Japan (A. Nomura, A. Nohara, M.K., H.T.).
  • Hayato Tada
    Department of Cardiovascular and Internal Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, Japan (A. Nomura, A. Nohara, M.K., H.T.).
  • Frederick E. Dewey
    Regeneron Genetics Center, Tarrytown, NY (S.M., T.M.T., F.E.D., A.B.).
  • David J. Carey
    Geisinger Health System, Danville, PA (J.B.L., H.L.K., D.J.C.).
  • Aris Baras
    Regeneron Genetics Center, Tarrytown, NY (S.M., T.M.T., F.E.D., A.B.).
  • Sekar Kathiresan
    Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (A.V.K., M.C., S.K.).

抄録

<jats:sec> <jats:title>Background</jats:title> <jats:p> Familial hypobetalipoproteinemia is a genetic disorder caused by rare protein-truncating variants (PTV) in the gene encoding <jats:italic>APOB</jats:italic> (apolipoprotein B), the major protein component of LDL (low-density lipoprotein) and triglyceride-rich lipoprotein particles. Whether heterozygous <jats:italic>APOB</jats:italic> deficiency is associated with decreased risk for coronary heart disease (CHD) is uncertain. We combined family-based and large scale gene-sequencing to characterize the association of rare PTVs in <jats:italic>APOB</jats:italic> with circulating LDL-C (LDL cholesterol), triglycerides, and risk for CHD. </jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p> We sequenced the <jats:italic>APOB</jats:italic> gene in 29 Japanese hypobetalipoproteinemia families, as well as 57 973 individuals derived from 12 CHD case-control studies—18 442 with early-onset CHD and 39 531 controls. We defined PTVs as variants that lead to a premature stop, disrupt canonical splice-sites, or lead to insertions/deletions that shift reading frame. We tested the association of rare <jats:italic>APOB</jats:italic> PTV carrier status with blood lipid levels and CHD. </jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p> Among 29 familial hypobetalipoproteinemia families, 8 families harbored <jats:italic>APOB</jats:italic> PTVs. Carrying 1 <jats:italic>APOB</jats:italic> PTV was associated with 55 mg/dL lower LDL-C ( <jats:italic>P</jats:italic> =3×10 <jats:sup>-5</jats:sup> ) and 53% lower triglyceride level ( <jats:italic>P</jats:italic> =2×10 <jats:sup>-4</jats:sup> ). Among 12 case-control studies, an <jats:italic>APOB</jats:italic> PTV was present in 0.038% of CHD cases as compared to 0.092% of controls. <jats:italic>APOB</jats:italic> PTV carrier status was associated with a 43 mg/dL lower LDL-C ( <jats:italic>P</jats:italic> =2×10 <jats:sup>-7</jats:sup> ), a 30% decrease in triglycerides ( <jats:italic>P</jats:italic> =5×10 <jats:sup>-4</jats:sup> ), and a 72% lower risk for CHD (odds ratio, 0.28; 95% CI, 0.12–0.64; <jats:italic>P</jats:italic> =0.002). </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p> Rare PTV mutations in <jats:italic>APOB</jats:italic> which are associated with lower LDL-C and reduced triglycerides also confer protection against CHD. </jats:p> </jats:sec>

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