title: Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks.
abstract: Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121*], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA.
authors: Gina M
authors: GM
authors: Peloso
authors: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA.
authors: Paul L
authors: PL
authors: Auer
authors: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA.
authors: Joshua C
authors: JC
authors: Bis
authors: Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
authors: Arend
authors: A
authors: Voorman
authors: Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors: Alanna C
authors: AC
authors: Morrison
authors: Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: Nathan O
authors: NO
authors: Stitziel
authors: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA.
authors: Jennifer A
authors: JA
authors: Brody
authors: Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Sumeet A
authors: SA
authors: Khetarpal
authors: Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Department of Biostatistics, Bioinformatics, and Systems Biology, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA.
authors: Jacy R
authors: JR
authors: Crosby
authors: Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors: Myriam
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authors: Fornage
authors: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3015CN, the Netherlands.
authors: Aaron
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authors: Isaacs
authors: Icelandic Heart Association, Kopavogur 201, Iceland.
authors: Johanna
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authors: Jakobsdottir
authors: Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: Mary F
authors: MF
authors: Feitosa
authors: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK; Department of Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK.
authors: Gail
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authors: Davies
authors: MRC Human Genetics, MRC IGMM, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors: Jennifer E
authors: JE
authors: Huffman
authors: Center for Public Health Genomics and Department of Public Health Sciences, University of Virginia, Charlottesville, VA 22908, USA.
authors: Ani
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authors: Manichaikul
authors: Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors: Brian
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authors: Wake Forest School of Medicine, Winston-Salem, NC 27106, USA.
authors: Kurt
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authors: Lohman
authors: Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors: Aron Y
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authors: Joon
authors: Icelandic Heart Association, Kopavogur 201, Iceland; Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland.
authors: Albert V
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authors: Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors: Megan L
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authors: Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Paolo
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authors: Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Valeska
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authors: Redon
authors: Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA; National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study, Framingham, MA 01702, USA.
authors: Serkalem
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authors: Demissie
authors: Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
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authors: Christopher
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authors: Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.
authors: Rebecca D
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authors: Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, IA 52242, USA.
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authors: Rachel H
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authors: Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, IA 52242, USA.
authors: Jennifer G
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authors: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA; Department of Epidemiology, University of Washington, Seattle, WA 98195, USA.
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authors: Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN 55454, USA.
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authors: Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN 55454, USA.
authors: James S
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authors: Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3015CN, the Netherlands.
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authors: Wake Forest School of Medicine, Winston-Salem, NC 27106, USA.
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authors: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK; Department of Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK.
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authors: Marioni
authors: Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3015CN, the Netherlands.
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authors: Oscar H
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authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; School of Medicine, Yale University, New Haven, CT 06510, USA.
authors: Aniruddh P
authors: AP
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authors: The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Yingchang
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authors: Department of Clinical Sciences in Malmö, Lund University, Clinical Research Center, Malmö 20502, Sweden.
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authors: The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
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authors: The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Erwin P
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authors: Bottinger
authors: Department of Clinical Sciences in Malmö, Lund University, Clinical Research Center, Malmö 20502, Sweden.
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authors: Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, University Hospital Malmö, Malmö 20502, Sweden.
authors: Marju
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authors: Orho-Melander
authors: The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Ruth J F
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authors: Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milano 20133, Italy.
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authors: Duga
authors: Associazione per lo Studio della Trombosi in Cardiologia (ASTC), Pavia 27100, Italy; Divisione di Cardiologia, Ospedale Niguarda, Milano 20162, Italy.
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authors: Merlini
authors: Department of Cardiovascular Medicine, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
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authors: Department of Cardiovascular Medicine, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
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authors: Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milano 20133, Italy.
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authors: Department of Medicine, University of Verona School of Medicine, Verona 37134, Italy.
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authors: Department of Medicine, University of Verona School of Medicine, Verona 37134, Italy.
authors: Nicola
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authors: Department of Obstetrics and Gynecology, Division of Urogynecology, Duke University, Durham, NC 27710, USA; Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
authors: Svati H
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authors: Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA; Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27701, USA.
authors: William E
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authors: Department of Biostatistics and Epidemiology, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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authors: Department of Cardiovascular Medicine, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK; Merck Sharp & Dohme Corp., Rahway, NJ 07065, USA.
authors: Hugh
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authors: Associazione per lo Studio della Trombosi in Cardiologia (ASTC), Pavia 27100, Italy; Divisione di Cardiologia, Azienda Ospedaliero-Universitaria di Parma, Parma 43100, Italy.
authors: Diego
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authors: Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
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authors: Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
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authors: Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55454, USA.
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authors: Jackson State University, Jackson, MS 39217, USA; Tougaloo College, Tougaloo, MS 39174, USA; Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
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authors: Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
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authors: Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors: Michael E
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authors: Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
authors: Leslie A
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authors: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK; Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh EH8 9JZ, UK.
authors: John M
authors: JM
authors: Starr
authors: Centre for Population Health Sciences, The University of Edinburgh Medical School, Edinburgh EH8 9AG, UK; Croatian Centre for Global Health, Faculty of Medicine, University of Split, Split 21000, Croatia.
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authors: Icelandic Heart Association, Kopavogur 201, Iceland.
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authors: National Institute on Aging, NIH, Bethesda, MD 20892, USA.
authors: Lenore J
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authors: Department of Cardiovascular Epidemiology and Population Genetics, National Center for Cardiovascular Investigation, Madrid 28049, Spain; IMDEA-Alimentacion, Madrid 28049, Spain; Nutrition and Genomics Laboratory, Jean Mayer-USDA Human Nutrition Research Center on Aging at Tufts University, Medford, MA 02155, USA.
authors: Jose M
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authors: National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study, Framingham, MA 01702, USA; Division of Intramural Research, NHLBI, NIH, Bethesda, MD 20892, USA.
authors: Daniel
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authors: Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
authors: Y-D Ida
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authors: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Epidemiology, University of Washington, Seattle, WA 98195, USA.
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authors: MRC Human Genetics, MRC IGMM, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors: Caroline
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authors: Hayward
authors: Department of Public Health, Faculty of Medicine, University of Split, Split 21000, Croatia.
authors: Ozren
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authors: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK; Department of Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK.
authors: Ian J
authors: IJ
authors: Deary
authors: Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
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authors: Wake Forest School of Medicine, Winston-Salem, NC 27106, USA.
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authors: Icelandic Heart Association, Kopavogur 201, Iceland; Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland.
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authors: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
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authors: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3015CN, the Netherlands.
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authors: Center for Public Health Genomics and Department of Public Health Sciences, University of Virginia, Charlottesville, VA 22908, USA.
authors: Stephen S
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authors: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA; Department of Epidemiology, University of Washington, Seattle, WA 98195, USA; Group Health Research Institute, Group Health Cooperative, Seattle, WA 98101, USA; Department of Health Services, University of Washington, Seattle, WA 98195, USA.
authors: Bruce M
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authors: Psaty
authors: Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
authors: Jerome I
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authors: Rotter
authors: Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study, Framingham, MA 01702, USA; Division of Intramural Research, NHLBI, NIH, Bethesda, MD 20892, USA; Cardiology Division, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: Christopher J
authors: CJ
authors: O'Donnell
authors: Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
authors: Kenneth
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authors: Rice
authors: Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Eric
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authors: Boerwinkle
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Cardiology Division, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: skathiresan@partners.org.
authors: Sekar
authors: S
authors: Kathiresan
authors: Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA; National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study, Framingham, MA 01702, USA. Electronic address: adrienne@bu.edu.
authors: L Adrienne
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authors: Cupples
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D000483:Alleles; D000818:Animals; D044383:Black People / Q000235:genetics; D008076:Cholesterol, HDL / Q000097:blood / Q000235:genetics*; D008078:Cholesterol, LDL / Q000097:blood / Q000235:genetics*; D015331:Cohort Studies; D003327:Coronary Disease / Q000097:blood / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D005815:Genetic Code; D014644:Genetic Variation; D006801:Humans; D016014:Linear Models; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D010641:Phenotype; D017422:Sequence Analysis, DNA; D013381:Subtilisins / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000097:blood*; D044465:White People / Q000235:genetics
chemical_list: D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D008869:Microtubule-Associated Proteins; D014280:Triglycerides; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C523923:PAFAH1B2 protein, human; C099101:PCSK7 protein, human; C490930:Pcsk7 protein, mouse; D013381:Subtilisins