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PLoS One. 2019 May 10;14(5):e0216222. doi: 10.1371/journal.pone.0216222. eCollection 2019.

Mendelian randomization evaluation of causal effects of fibrinogen on incident coronary heart disease.

Author information

1
Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
2
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
3
Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Houston, United States of America.
4
Department of Medicine, University of Washington, Health Sciences Bldg, Seattle, Washington, United States of America.
5
Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Framingham, MA, United States of America.
6
The Framingham Heart Study, Framingham, MA, United States of America.
7
GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Broadway, Baltimore, MD, United States of America.
8
Epidemiology, University of Michigan, Ann Arbor, Michigan, United States of America.
9
Division of Preventative Medicine, Brigham and Women's Hospital, Boston, MA, United States of America.
10
Institute for Translational Genomics and Population Sciences, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, United States of America.
11
Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany.
12
Institute of Nutrition, Friedrich-Schiller University Jena, Jena, Germany.
13
Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt University Greifswald, Griefswald, Germany.
14
DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.
15
Research Group Computational Systems Medicine, Chair of Experimental Bioinformatics, TUM School of Life Sciences, Technical University of Munich, Freising-Weihenstephan, Germany.
16
Department of Internal Medicine B, University Medicine Greifswald, Ferdinand-Sauerbruch-Straße, Greifswald, Germany.
17
Institute of Clinical Chemistry and Laboratory Medicine, University of Medicine Griefswald, Ferdinand-Sauerbruch-Straße, Greifswald, Germany.
18
Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.
19
Postgraduate Program in Epidemiology, Federal University of Pelotas, Pelotas, Brazil.
20
Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
21
DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
22
Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany.
23
Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
24
Department of Internal Medicine II, University of Ulm Medical Center, Ulm, Germany.
25
Deutsches Herzzentrum München, Technische Universität München, Munich, Germany.
26
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
27
Institute of Human Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
28
Institute of Human Genetics, Technische Universität München, Munich, Germany.
29
University of Minnesota School of Medicine, Minneapolis, MN, United States of America.
30
Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, Houston, United States of America.
31
University of Minnesota School of Public Health, Minneapolis, MN, United States of America.
32
Office of Biostatistics Research, Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States of America.
33
Department of Hematology, Erasmus University Medical Center, Rotterdam, CND, Netherlands.
34
Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, CN, Netherlands.
35
Department of Biostatistics, University of Washington, Health Sciences Bldg, Seattle, WA, United States of America.
36
Department of Epidemiology, University of Washington, Health Sciences Bldg, Seattle, WA, United States of America.
37
Department of Health Services, University of Washington, Health Sciences Bldg, Seattle, WA, United States of America.
38
Group Health Research Institute, Group Health Cooperative, Seattle, WA, United States of America.
39
Division of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins University School of Medicine, N. Broadway, Baltimore, MD, United States of America.
40
Department of Epidemiology, Mayo Clinic, Rochester, MN, United States of America.
41
Pathology and Laboratory Medicine, The University of Vermont College of Medicine, Col Research Facility, Burlington, VT, United States of America.
42
Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, Netherlands.
43
BHF Glasgow Cardiovascular Research Centre, Faculty of Medicine, Glasgow, United Kingdom.
44
Department of Cardiology, Leiden University Medical Center, Leiden, Netherlands.
45
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, N. Broadway, Baltimore, MD, United States of America.
46
Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim, Germany.
47
Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
48
Department of Epidemiology and Biostatistics, Imperial College London, Norfolk Place, London, United Kingdom.
49
Cardiology Section Administration, Boston VA Healthcare System, West Roxbury, MA, United States of America.
50
Seattle Epidemiologic Research and Information Center, Department of Veteran Affairs Office of Research and Development, Columbian Way, Seattle, WA, United States of America.

Abstract

BACKGROUND:

Fibrinogen is an essential hemostatic factor and cardiovascular disease risk factor. Early attempts at evaluating the causal effect of fibrinogen on coronary heart disease (CHD) and myocardial infraction (MI) using Mendelian randomization (MR) used single variant approaches, and did not take advantage of recent genome-wide association studies (GWAS) or multi-variant, pleiotropy robust MR methodologies.

METHODS AND FINDINGS:

We evaluated evidence for a causal effect of fibrinogen on both CHD and MI using MR. We used both an allele score approach and pleiotropy robust MR models. The allele score was composed of 38 fibrinogen-associated variants from recent GWAS. Initial analyses using the allele score used a meta-analysis of 11 European-ancestry prospective cohorts, free of CHD and MI at baseline, to examine incidence CHD and MI. We also applied 2 sample MR methods with data from a prevalent CHD and MI GWAS. Results are given in terms of the hazard ratio (HR) or odds ratio (OR), depending on the study design, and associated 95% confidence interval (CI). In single variant analyses no causal effect of fibrinogen on CHD or MI was observed. In multi-variant analyses using incidence CHD cases and the allele score approach, the estimated causal effect (HR) of a 1 g/L higher fibrinogen concentration was 1.62 (CI = 1.12, 2.36) when using incident cases and the allele score approach. In 2 sample MR analyses that accounted for pleiotropy, the causal estimate (OR) was reduced to 1.18 (CI = 0.98, 1.42) and 1.09 (CI = 0.89, 1.33) in the 2 most precise (smallest CI) models, out of 4 models evaluated. In the 2 sample MR analyses for MI, there was only very weak evidence of a causal effect in only 1 out of 4 models.

CONCLUSIONS:

A small causal effect of fibrinogen on CHD is observed using multi-variant MR approaches which account for pleiotropy, but not single variant MR approaches. Taken together, results indicate that even with large sample sizes and multi-variant approaches MR analyses still cannot exclude the null when estimating the causal effect of fibrinogen on CHD, but that any potential causal effect is likely to be much smaller than observed in epidemiological studies.

Conflict of interest statement

BMP reports serving on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. WK reports personal fees from AstraZeneca Novartis, Pfizer, The Medicines Company, GlaxoSmithKline, DalCor, Sanofi, Berlin-Chemie, Kowa, and Amgen. WK also reports grants and non-financial support from Abbott, Roche Diagnostics, Beckmann, and Singulex. All reports from WK are outside the submitted work. WM reports grants and personal fees from Siemens Diagnostics, Aegerion Pharmaceuticals, AMGEN, AstraZeneca, Danone Research, Sanofi/Genzyme, Pfizer, BASF, and Numares. WM reports personal fees from Hoffmann LaRoche, MSD, Sanofi, and Alexion. WM is employed by Synlab Holding Deutschland GmbH and all reports by WM are outside the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

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