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Education and coronary heart disease: mendelian randomisation study

BMJ 2017; 358 doi: https://doi.org/10.1136/bmj.j3542 (Published 30 August 2017) Cite this as: BMJ 2017;358:j3542
  1. Taavi Tillmann, Wellcome Trust fellow (joint first author)1,
  2. Julien Vaucher, physician and clinical research fellow (joint first author)2,
  3. Aysu Okbay, postdoctoral researcher3,
  4. Hynek Pikhart, reader1,
  5. Anne Peasey, senior teaching fellow1,
  6. Ruzena Kubinova, director4,
  7. Andrzej Pajak, professor5,
  8. Abdonas Tamosiunas, professor6,
  9. Sofia Malyutina, professor7 8,
  10. Fernando Pires Hartwig, research associate9 10,
  11. Krista Fischer, senior researcher11,
  12. Giovanni Veronesi, statistician12,
  13. Tom Palmer, lecturer13,
  14. Jack Bowden, senior research fellow10,
  15. George Davey Smith, professor10 14,
  16. Martin Bobak, professor1,
  17. Michael V Holmes, university research lecturer10 15 16 17
  1. 1Department of Epidemiology and Public Health, University College London, London, UK
  2. 2Department of Internal Medicine, Lausanne University Hospital, Lausanne, Switzerland
  3. 3Department of Complex Trait Genetics, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
  4. 4Centre for Environmental Health Monitoring, National Institute of Public Health, Prague, Czech Republic
  5. 5Chair of Epidemiology and Population Studies, Institute of Public Health, Faculty of Health Sciences, Jagiellonian University Medical College, Krakow, Poland
  6. 6Institute of Cardiology, Lithuanian University of Health Sciences, Kaunas, Lithuania
  7. 7Research Institute of Internal and Preventive Medicine, Branch of the Institute of Cytology and Genetics, SB RAS, Novosibirsk, Russia
  8. 8Novosibirsk State Medical University, Novosibirsk, Russia
  9. 9Postgraduate Programme in Epidemiology, Federal University of Pelotas, Pelotas, Brazil
  10. 10Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
  11. 11Estonian Genome Center, University of Tartu, Tartu, Estonia
  12. 12Research Center in Epidemiology and Preventive Medicine, University of Insubria, Varese, Italy
  13. 13Department of Mathematics and Statistics, Lancaster University, Lancaster, UK
  14. 14School of Social and Community Medicine, University of Bristol, Bristol, UK
  15. 15Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, Big Data Institute, University of Oxford, Oxford, UK
  16. 16Medical Research Council Population Health Research Unit at the University of Oxford, Oxford, UK
  17. 17National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospital, Oxford, UK
  1. Correspondence to: T Tillmann t.tillmann{at}ucl.ac.uk
  • Accepted 9 July 2017

Abstract

Objective To determine whether educational attainment is a causal risk factor in the development of coronary heart disease.

Design Mendelian randomisation study, using genetic data as proxies for education to minimise confounding.

Setting The main analysis used genetic data from two large consortia (CARDIoGRAMplusC4D and SSGAC), comprising 112 studies from predominantly high income countries. Findings from mendelian randomisation analyses were then compared against results from traditional observational studies (164 170 participants). Finally, genetic data from six additional consortia were analysed to investigate whether longer education can causally alter the common cardiovascular risk factors.

Participants The main analysis was of 543 733 men and women (from CARDIoGRAMplusC4D and SSGAC), predominantly of European origin.

Exposure A one standard deviation increase in the genetic predisposition towards higher education (3.6 years of additional schooling), measured by 162 genetic variants that have been previously associated with education.

Main outcome measure Combined fatal and non-fatal coronary heart disease (63 746 events in CARDIoGRAMplusC4D).

Results Genetic predisposition towards 3.6 years of additional education was associated with a one third lower risk of coronary heart disease (odds ratio 0.67, 95% confidence interval 0.59 to 0.77; P=3×10−8). This was comparable to findings from traditional observational studies (prevalence odds ratio 0.73, 0.68 to 0.78; incidence odds ratio 0.80, 0.76 to 0.83). Sensitivity analyses were consistent with a causal interpretation in which major bias from genetic pleiotropy was unlikely, although this remains an untestable possibility. Genetic predisposition towards longer education was additionally associated with less smoking, lower body mass index, and a favourable blood lipid profile.

Conclusions This mendelian randomisation study found support for the hypothesis that low education is a causal risk factor in the development of coronary heart disease. Potential mechanisms could include smoking, body mass index, and blood lipids. In conjunction with the results from studies with other designs, these findings suggest that increasing education may result in substantial health benefits.

Footnotes

  • We are grateful to the eight GWAS consortia (especially SSGAC and CARDIoGRAMplusC4D) for publicly sharing the genetic data we used in our causal analysis, to Reedik Mägi for assistance on LD score regression, and to Daniel J Benjamin for comments on an earlier draft of this article.

  • Contributors: TT and JV contributed equally to this paper and are joint first authors. TT had the idea for the study. AO obtained the genetic data. HP, AP, RK, AP, AT, SM, and KF obtained the observational data. MVH, GDS, JB, FPH, TP, and GV developed the study methods. JV, TT, FPH, and MVH did the analysis. All authors were involved in interpreting the data. TT, JV, and MVH wrote the first draft of the manuscript, and all authors critically revised it. TT, JV, and MVH are the guarantors.

  • Funding: TT is funded by a Wellcome Trust fellowship (106554/Z/14/Z); JV is supported by the Swiss National Science Foundation (P2LAP3_155086); the HAPIEE study is supported by the Wellcome Trust (064947/Z/01/Z, WT081081), the US National Institute on Aging (1R01 AG23522), the MacArthur Foundation (Health and Social Upheaval network), and the Russian Science Foundation (14-45-00030); the MORGAM Project was supported by the European Union’s Seventh Framework Programme (HEALTH-F3-2010-242244, HEALTH-F2-2011-278913); GDS works in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol (MC_UU_12013/1); JB is supported by a Medical Research Council (MRC) methodology research fellowship (grant MR/N501906/1); AO is supported by a European Research Council consolidator grant (647648 EdGe); MVH is supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre and works in the MRC Population Health Research Unit at the University of Oxford that receives funding from the UK MRC. The funders had no role in the study design, data collection, analysis, interpretation, or writing, nor in the decision to submit the article for publication.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: support for the submitted work as detailed above; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: Participants gave informed consent for data sharing, as described in each of the discovery genome-wide association studies. Additional ethical approval was not needed for this study.

  • Transparency: The lead authors affirm that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

  • Data sharing: All of the summary level data used are available for instant download at the public repositories listed in table 1. The statistical code is available from the corresponding authors at t.tillmann@ucl.ac.uk and julien.vaucher@chuv.ch.

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/.

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