Meta-Analysis

. 2015 Mar 1;36(9):539-50.

doi: 10.1093/eurheartj/eht571. Epub 2014 Jan 27.

Mendelian randomization of blood lipids for coronary heart disease

Michael V Holmes¹, Folkert W Asselbergs², Tom M Palmer³, Fotios Drenos⁴, Matthew B Lanktree⁵, Christopher P Nelson⁶, Caroline E Dale⁷, Sandosh Padmanabhan⁸, Chris Finan⁹, Daniel I Swerdlow⁹, Vinicius Tragante¹⁰, Erik P A van Iperen¹¹, Suthesh Sivapalaratnam¹², Sonia Shah¹³, Clara C Elbers¹⁴, Tina Shah⁹, Jorgen Engmann⁹, Claudia Giambartolomei¹³, Jon White¹³, Delilah Zabaneh¹³, Reecha Sofat⁹, Stela McLachlan¹⁵; UCLEB consortium; Pieter A Doevendans¹⁶, Anthony J Balmforth¹⁷, Alistair S Hall¹⁷, Kari E North¹⁸, Berta Almoguera¹⁹, Ron C Hoogeveen²⁰, Mary Cushman²¹, Myriam Fornage²², Sanjay R Patel²³, Susan Redline²³, David S Siscovick²⁴, Michael Y Tsai²⁵, Konrad J Karczewski²⁶, Marten H Hofker²⁷, W Monique Verschuren²⁸, Michiel L Bots²⁹, Yvonne T van der Schouw²⁹, Olle Melander³⁰, Anna F Dominiczak⁸, Richard Morris³¹, Yoav Ben-Shlomo³², Jackie Price¹⁵, Meena Kumari⁹, Jens Baumert³³, Annette Peters³³, Barbara Thorand³³, Wolfgang Koenig³⁴, Tom R Gaunt³⁵, Steve E Humphries³⁶, Robert Clarke³⁷, Hugh Watkins³⁸, Martin Farrall³⁸, James G Wilson³⁹, Stephen S Rich⁴⁰, Paul I W de Bakker⁴¹, Leslie A Lange⁴², George Davey Smith³⁵, Alex P Reiner⁴³, Philippa J Talmud³⁶, Mika Kivimäki⁴⁴, Debbie A Lawlor³⁵, Frank Dudbridge⁷, Nilesh J Samani⁶, Brendan J Keating⁴⁵, Aroon D Hingorani⁹, Juan P Casas⁴⁶

Collaborators, Affiliations

Collaborators

UCLEB consortium:
Tina Shah, Jorgen Engmann, Caroline E Dale, Sonia Shah, Jon White, Claudia Giambartolomei, Stela McLachlan, Delilah Zabaneh, Alana Cavadino, Chris Finan, Andrew Wong, Antoinette Amuzu, Ken Ong, Tom R Gaunt, Michael V Holmes, Helen Warren, Daniel I Swerdlow, Teri-Louise Davies, Fotios Drenos, Reecha Sofat, Mary Cushman, Shah Ebrahim, Debbie A Lawlor, Philippa J Talmud, Steve E Humphries, Christine Power, Elina Hypponen, Richard Morris, Rebecca Hardy, Diana Kuh, Nicholas Wareham, Claudia Langenberg, Yoav BenShlomo, Peter Whincup, Richard Morris, Jackie Price, Meena Kumari, Mika Kivimäki, Frank Dudbridge, Juan P Casas, Aroon D Hingorani

Affiliations

¹ 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.
² 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.
³ Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK.
⁴ 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.
⁵ Department of Medicine, McMaster University, Hamilton, ON, Canada L8S 4L8.
⁶ Department of Cardiovascular Sciences, University of Leicester, Leicester, UK NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
⁷ Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
⁸ Institute of Cardiovascular and Medical Sciences, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK.
⁹ Genetic Epidemiology Group, Institute of Cardiovacular Science, Faculty of Population Healh Sciences, University College London, 1-19 Torrington Place, London WC1E 6BT, UK.
¹⁰ 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.
¹¹ 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.
¹² Department of Vascular Medicine, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands.
¹³ Department of Genetics Environment and Evolution, UCL Genetics Institute, 2nd Floor, Darwin Building, Gower Street, London WC1E 6BT, UK.
¹⁴ 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.
¹⁵ Centre for Population Health Sciences, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK.
¹⁶ Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.
¹⁷ Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, UK.
¹⁸ Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
¹⁹ Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
²⁰ Baylor College of Medicine, Department of Medicine, Division of Atherosclerosis and Vascular Medicine, Houston, TX 77030, USA.
²¹ 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.
²² The University of Texas Health Science Center at Houston, Houston, TX, USA.
²³ Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
²⁴ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA Department of Epidemiology, University of Washington, Seattle, WA, USA.
²⁵ Department of Laboratory Medicine and Pathology, University of Minnesota.
²⁶ Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
²⁷ Department Pathology and Medical Biology, Medical Biology Division, Molecular Genetics, University Medical Center Groningen and Groningen University, Groningen, The Netherlands.
²⁸ Centre for Prevention and Health Services Research at National Institute for Public Health and the Environment, Utrecht, The Netherlands.
²⁹ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
³⁰ Lund University, Malmö, Sweden.
³¹ Department of Primary Care and Population Health, UCL, Royal Free Campus, Rowland Hill St, London, UK.
³² School of Social and Community Medicine, University of Bristol.
³³ Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
³⁴ Department of Internal Medicine II-Cardiology, University of Ulm Medical Center, Ulm, Germany.
³⁵ MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
³⁶ Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, Rayne Building, London WC1E 6JF, UK.
³⁷ Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
³⁸ Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
³⁹ Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
⁴⁰ Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA.
⁴¹ 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.
⁴² Department of Genetics, University of North Carolina School of Medicine at Chapel Hill, Chapel Hill,NC27514, USA.
⁴³ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
⁴⁴ Department of Epidemiology and Public Health, University College London, 1-19 Torrington Place, London WC1E 6BT, UK.
⁴⁵ 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.
⁴⁶ 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.

PMID: 24474739
PMCID: PMC4344957
DOI: 10.1093/eurheartj/eht571

Meta-Analysis

Mendelian randomization of blood lipids for coronary heart disease

Michael V Holmes et al. Eur Heart J. 2015.

. 2015 Mar 1;36(9):539-50.

doi: 10.1093/eurheartj/eht571. Epub 2014 Jan 27.

Authors

Collaborators

UCLEB consortium:
Tina Shah, Jorgen Engmann, Caroline E Dale, Sonia Shah, Jon White, Claudia Giambartolomei, Stela McLachlan, Delilah Zabaneh, Alana Cavadino, Chris Finan, Andrew Wong, Antoinette Amuzu, Ken Ong, Tom R Gaunt, Michael V Holmes, Helen Warren, Daniel I Swerdlow, Teri-Louise Davies, Fotios Drenos, Reecha Sofat, Mary Cushman, Shah Ebrahim, Debbie A Lawlor, Philippa J Talmud, Steve E Humphries, Christine Power, Elina Hypponen, Richard Morris, Rebecca Hardy, Diana Kuh, Nicholas Wareham, Claudia Langenberg, Yoav BenShlomo, Peter Whincup, Richard Morris, Jackie Price, Meena Kumari, Mika Kivimäki, Frank Dudbridge, Juan P Casas, Aroon D Hingorani

Affiliations

¹ 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.
² 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.
³ Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK.
⁴ 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.
⁵ Department of Medicine, McMaster University, Hamilton, ON, Canada L8S 4L8.
⁶ Department of Cardiovascular Sciences, University of Leicester, Leicester, UK NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
⁷ Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
⁸ Institute of Cardiovascular and Medical Sciences, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK.
⁹ Genetic Epidemiology Group, Institute of Cardiovacular Science, Faculty of Population Healh Sciences, University College London, 1-19 Torrington Place, London WC1E 6BT, UK.
¹⁰ 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.
¹¹ 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.
¹² Department of Vascular Medicine, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands.
¹³ Department of Genetics Environment and Evolution, UCL Genetics Institute, 2nd Floor, Darwin Building, Gower Street, London WC1E 6BT, UK.
¹⁴ 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.
¹⁵ Centre for Population Health Sciences, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK.
¹⁶ Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.
¹⁷ Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, UK.
¹⁸ Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
¹⁹ Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
²⁰ Baylor College of Medicine, Department of Medicine, Division of Atherosclerosis and Vascular Medicine, Houston, TX 77030, USA.
²¹ 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.
²² The University of Texas Health Science Center at Houston, Houston, TX, USA.
²³ Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
²⁴ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA Department of Epidemiology, University of Washington, Seattle, WA, USA.
²⁵ Department of Laboratory Medicine and Pathology, University of Minnesota.
²⁶ Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
²⁷ Department Pathology and Medical Biology, Medical Biology Division, Molecular Genetics, University Medical Center Groningen and Groningen University, Groningen, The Netherlands.
²⁸ Centre for Prevention and Health Services Research at National Institute for Public Health and the Environment, Utrecht, The Netherlands.
²⁹ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
³⁰ Lund University, Malmö, Sweden.
³¹ Department of Primary Care and Population Health, UCL, Royal Free Campus, Rowland Hill St, London, UK.
³² School of Social and Community Medicine, University of Bristol.
³³ Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
³⁴ Department of Internal Medicine II-Cardiology, University of Ulm Medical Center, Ulm, Germany.
³⁵ MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
³⁶ Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, Rayne Building, London WC1E 6JF, UK.
³⁷ Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
³⁸ Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
³⁹ Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
⁴⁰ Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA.
⁴¹ 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.
⁴² Department of Genetics, University of North Carolina School of Medicine at Chapel Hill, Chapel Hill,NC27514, USA.
⁴³ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
⁴⁴ Department of Epidemiology and Public Health, University College London, 1-19 Torrington Place, London WC1E 6BT, UK.
⁴⁵ 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.
⁴⁶ 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.

PMID: 24474739
PMCID: PMC4344957
DOI: 10.1093/eurheartj/eht571

Abstract

Aims: 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.

Methods and 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).

Conclusion: The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain.

Keywords: Aetiology; Epidemiology; Heart disease; Lipids; Mendelian randomization.

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Figures

**Figure 1**
Meta-analysis pooled estimates of the association of the unrestricted and restricted allele scores with target and non-target lipid traits. Estimates were obtained from prospective cohorts genotyped using the ITMAT Broad Institute CARe consortium CardioChip array (detailed in Supplementary material online, *Table S1*). A lower limit of 0 was imposed on the R² values. Mean diff, mean difference comparing top to bottom quintile of each allele score. R² = proportion of variable of the lipid traits explained by each allele score. TG, triglycerides.

**Figure 2**
Meta-analysis pooled estimates for the effect of a 1 unit increase in blood lipid traits on coronary heart disease risk using instrumental variable analysis incorporating data from all studies. Estimates were derived incorporating data on the association between the allele scores and blood lipid traits only from prospective cohorts (in which most individuals were free from disease when lipid traits were measured) and applying this estimate to all studies with data on the association between the scores and coronary heart disease (including case–control studies). See Methods for further details. TG, triglycerides.

**Figure 3**
Meta-analysis pooled estimates for the effect of a 1 unit increase in blood lipid traits on combined incident/prevalent coronary heart disease risk using instrumental variable analysis with the unrestricted allele score, adjusted for non-target traits and statin use. Analysis was conducted in prospective cohorts with instrumental variables regression analysis. TG, triglycerides.

**Figure 4**
Meta-analysis pooled estimate for the effect of a 1 unit increase in blood lipid traits on carotid intima medial thickness. The four population-based prospective cohorts with carotid intima medial thickness traits were CHS, FHS, MESA, and Whitehall II (Supplementary material online, *Table S4*).

See this image and copyright information in PMC

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Mendelian randomization of blood lipids for coronary heart disease

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Mendelian randomization of blood lipids for coronary heart disease

Authors

Collaborators

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Abstract

Figures

References

Publication types

MeSH terms

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Grants and funding

LinkOut - more resources

Full Text Sources

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Medical

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