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Am J Hum Genet. 2014 Feb 6;94(2):223-32. doi: 10.1016/j.ajhg.2014.01.009.

Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks.

Author information

1
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.
2
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.
3
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA.
4
Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
5
Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
6
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.
7
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
8
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.
9
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.
10
Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3015CN, the Netherlands.
11
Icelandic Heart Association, Kopavogur 201, Iceland.
12
Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
13
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK; Department of Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK.
14
MRC Human Genetics, MRC IGMM, University of Edinburgh, Edinburgh EH4 2XU, UK.
15
Center for Public Health Genomics and Department of Public Health Sciences, University of Virginia, Charlottesville, VA 22908, USA.
16
Wake Forest School of Medicine, Winston-Salem, NC 27106, USA.
17
Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
18
Icelandic Heart Association, Kopavogur 201, Iceland; Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland.
19
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.
20
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
21
Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.
22
Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, IA 52242, USA.
23
Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.
24
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA; Department of Epidemiology, University of Washington, Seattle, WA 98195, USA.
25
Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN 55454, USA.
26
Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3015CN, the Netherlands.
27
National Institute on Aging, NIH, Bethesda, MD 20892, USA.
28
Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
29
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.
30
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.
31
Department of Clinical Sciences in Malmö, Lund University, Clinical Research Center, Malmö 20502, Sweden.
32
The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
33
Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, University Hospital Malmö, Malmö 20502, Sweden.
34
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.
35
Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milano 20133, Italy.
36
Associazione per lo Studio della Trombosi in Cardiologia (ASTC), Pavia 27100, Italy; Divisione di Cardiologia, Ospedale Niguarda, Milano 20162, Italy.
37
Department of Cardiovascular Medicine, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
38
Department of Medicine, University of Verona School of Medicine, Verona 37134, Italy.
39
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.
40
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.
41
Department of Biostatistics and Epidemiology, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
42
Atherogenomics Laboratory, Division of Cardiology, University of Ottawa Heart Institute, Ottawa, ON K1Y 4W7, Canada.
43
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.
44
Associazione per lo Studio della Trombosi in Cardiologia (ASTC), Pavia 27100, Italy; Divisione di Cardiologia, Azienda Ospedaliero-Universitaria di Parma, Parma 43100, Italy.
45
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55454, USA.
46
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.
47
Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
48
Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
49
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.
50
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.
51
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.
52
National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study, Framingham, MA 01702, USA; Division of Intramural Research, NHLBI, NIH, Bethesda, MD 20892, USA.
53
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Epidemiology, University of Washington, Seattle, WA 98195, USA.
54
Department of Public Health, Faculty of Medicine, University of Split, Split 21000, Croatia.
55
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
56
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.
57
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.
58
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.
59
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.
60
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.

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.

PMID:
24507774
PMCID:
PMC3928662
DOI:
10.1016/j.ajhg.2014.01.009
[Indexed for MEDLINE]
Free PMC Article

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