Mendelian randomization of blood lipids for coronary heart disease.
OBJECTIVE
To investigate the causal role of high-density lipoprotein cholesterol (HDL-C) and triglycerides in coronary heart disease (CHD) using multiple instrumental variables for Mendelian randomization.


RESULTS
We developed weighted allele scores based on single nucleotide polymorphisms (SNPs) with established associations with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C). For each trait, we constructed two scores. The first was unrestricted, including all independent SNPs associated with the lipid trait identified from a prior meta-analysis (threshold P < 2 × 10(-6)); and the second a restricted score, filtered to remove any SNPs also associated with either of the other two lipid traits at P ≤ 0.01. Mendelian randomization meta-analyses were conducted in 17 studies including 62,199 participants and 12,099 CHD events. Both the unrestricted and restricted allele scores for LDL-C (42 and 19 SNPs, respectively) associated with CHD. For HDL-C, the unrestricted allele score (48 SNPs) was associated with CHD (OR: 0.53; 95% CI: 0.40, 0.70), per 1 mmol/L higher HDL-C, but neither the restricted allele score (19 SNPs; OR: 0.91; 95% CI: 0.42, 1.98) nor the unrestricted HDL-C allele score adjusted for triglycerides, LDL-C, or statin use (OR: 0.81; 95% CI: 0.44, 1.46) showed a robust association. For triglycerides, the unrestricted allele score (67 SNPs) and the restricted allele score (27 SNPs) were both associated with CHD (OR: 1.62; 95% CI: 1.24, 2.11 and 1.61; 95% CI: 1.00, 2.59, respectively) per 1-log unit increment. However, the unrestricted triglyceride score adjusted for HDL-C, LDL-C, and statin use gave an OR for CHD of 1.01 (95% CI: 0.59, 1.75).


CONCLUSIONS
The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain.
Genetic Epidemiology Group, Institute of Cardiovacular Science, Faculty of Population Healh Sciences, University College London, 1-19 Torrington Place, London WC1E 6BT, UK Division of Transplant Surgery, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce St, Philadelphia, PA 19104, USA mvholmes@gmail.com.
Michael V
MV
Holmes
Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, UK.
Folkert W
FW
Asselbergs
Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK.
Tom M
TM
Palmer
Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, Rayne Building, London WC1E 6JF, UK MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
Fotios
F
Drenos
Department of Medicine, McMaster University, Hamilton, ON, Canada L8S 4L8.
Matthew B
MB
Lanktree
Department of Cardiovascular Sciences, University of Leicester, Leicester, UK NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
Christopher P
CP
Nelson
Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
Caroline E
CE
Dale
Institute of Cardiovascular and Medical Sciences, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK.
Sandosh
S
Padmanabhan
Genetic Epidemiology Group, Institute of Cardiovacular Science, Faculty of Population Healh Sciences, University College London, 1-19 Torrington Place, London WC1E 6BT, UK.
Chris
C
Finan
Genetic Epidemiology Group, Institute of Cardiovacular Science, Faculty of Population Healh Sciences, University College London, 1-19 Torrington Place, London WC1E 6BT, UK.
Daniel I
DI
Swerdlow
Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands Department of Medical Genetics, Division of Biomedical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Vinicius
V
Tragante
Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, Amsterdam, The Netherlands.
Erik P A
EP
van Iperen
Department of Vascular Medicine, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands.
Suthesh
S
Sivapalaratnam
Department of Genetics Environment and Evolution, UCL Genetics Institute, 2nd Floor, Darwin Building, Gower Street, London WC1E 6BT, UK.
Sonia
S
Shah
Department of Medical Genetics, Division of Biomedical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Clara C
CC
Elbers
Genetic Epidemiology Group, Institute of Cardiovacular Science, Faculty of Population Healh Sciences, University College London, 1-19 Torrington Place, London WC1E 6BT, UK.
Tina
T
Shah
Genetic Epidemiology Group, Institute of Cardiovacular Science, Faculty of Population Healh Sciences, University College London, 1-19 Torrington Place, London WC1E 6BT, UK.
Jorgen
J
Engmann
Department of Genetics Environment and Evolution, UCL Genetics Institute, 2nd Floor, Darwin Building, Gower Street, London WC1E 6BT, UK.
Claudia
C
Giambartolomei
Department of Genetics Environment and Evolution, UCL Genetics Institute, 2nd Floor, Darwin Building, Gower Street, London WC1E 6BT, UK.
Jon
J
White
Department of Genetics Environment and Evolution, UCL Genetics Institute, 2nd Floor, Darwin Building, Gower Street, London WC1E 6BT, UK.
Delilah
D
Zabaneh
Genetic Epidemiology Group, Institute of Cardiovacular Science, Faculty of Population Healh Sciences, University College London, 1-19 Torrington Place, London WC1E 6BT, UK.
Reecha
R
Sofat
Centre for Population Health Sciences, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK.
Stela
S
McLachlan
Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.
Pieter A
PA
Doevendans
Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, UK.
Anthony J
AJ
Balmforth
Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, UK.
Alistair S
AS
Hall
Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
Kari E
KE
North
Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Berta
B
Almoguera
Baylor College of Medicine, Department of Medicine, Division of Atherosclerosis and Vascular Medicine, Houston, TX 77030, USA.
Ron C
RC
Hoogeveen
Department of Medicine, University of Vermont, 208 South Park Dr, Colchester, VT 05446, USA Department of Pathology, University of Vermont, 208 South Park Dr, Colchester, VT 05446, USA.
Mary
M
Cushman
The University of Texas Health Science Center at Houston, Houston, TX, USA.
Myriam
M
Fornage
Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Sanjay R
SR
Patel
Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Susan
S
Redline
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA Department of Epidemiology, University of Washington, Seattle, WA, USA.
David S
DS
Siscovick
Department of Laboratory Medicine and Pathology, University of Minnesota.
Michael Y
MY
Tsai
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
Konrad J
KJ
Karczewski
Department Pathology and Medical Biology, Medical Biology Division, Molecular Genetics, University Medical Center Groningen and Groningen University, Groningen, The Netherlands.
Marten H
MH
Hofker
Centre for Prevention and Health Services Research at National Institute for Public Health and the Environment, Utrecht, The Netherlands.
W Monique
WM
Verschuren
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
Michiel L
ML
Bots
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
Yvonne T
YT
van der Schouw
Lund University, Malmö, Sweden.
Olle
O
Melander
Institute of Cardiovascular and Medical Sciences, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK.
Anna F
AF
Dominiczak
Department of Primary Care and Population Health, UCL, Royal Free Campus, Rowland Hill St, London, UK.
Richard
R
Morris
School of Social and Community Medicine, University of Bristol.
Yoav
Y
Ben-Shlomo
Centre for Population Health Sciences, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK.
Jackie
J
Price
Genetic Epidemiology Group, Institute of Cardiovacular Science, Faculty of Population Healh Sciences, University College London, 1-19 Torrington Place, London WC1E 6BT, UK.
Meena
M
Kumari
Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Jens
J
Baumert
Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Annette
A
Peters
Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Barbara
B
Thorand
Department of Internal Medicine II-Cardiology, University of Ulm Medical Center, Ulm, Germany.
Wolfgang
W
Koenig
MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
Tom R
TR
Gaunt
Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, Rayne Building, London WC1E 6JF, UK.
Steve E
SE
Humphries
Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
Robert
R
Clarke
Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
Hugh
H
Watkins
Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
Martin
M
Farrall
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
James G
JG
Wilson
Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA.
Stephen S
SS
Rich
Department of Medical Genetics, Division of Biomedical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
Paul I W
PI
de Bakker
Department of Genetics, University of North Carolina School of Medicine at Chapel Hill, Chapel Hill,NC27514, USA.
Leslie A
LA
Lange
MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
George
G
Davey Smith
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Alex P
AP
Reiner
Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, Rayne Building, London WC1E 6JF, UK.
Philippa J
PJ
Talmud
Department of Epidemiology and Public Health, University College London, 1-19 Torrington Place, London WC1E 6BT, UK.
Mika
M
Kivimäki
MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
Debbie A
DA
Lawlor
Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
Frank
F
Dudbridge
Department of Cardiovascular Sciences, University of Leicester, Leicester, UK NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
Nilesh J
NJ
Samani
Division of Transplant Surgery, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce St, Philadelphia, PA 19104, USA Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA, USA Department of Paediatrics, School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Brendan J
BJ
Keating
Genetic Epidemiology Group, Institute of Cardiovacular Science, Faculty of Population Healh Sciences, University College London, 1-19 Torrington Place, London WC1E 6BT, UK.
Aroon D
AD
Hingorani
Genetic Epidemiology Group, Institute of Cardiovacular Science, Faculty of Population Healh Sciences, University College London, 1-19 Torrington Place, London WC1E 6BT, UK Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
Juan P
JP
Casas
D016022:Case-Control Studies; D008076:Cholesterol, HDL / Q000235:genetics*; D003324:Coronary Artery Disease / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D060005:Genotyping Techniques; D006801:Humans; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D018570:Risk Assessment; D014280:Triglycerides / Q000235:genetics*
D008076:Cholesterol, HDL; D014280:Triglycerides
Aetiology; Epidemiology; Heart disease; Lipids; Mendelian randomization