Understanding the consequences of education inequality on cardiovascular disease: mendelian randomisation studyBMJ 2019; 365 doi: https://doi.org/10.1136/bmj.l1855 (Published 22 May 2019) Cite this as: BMJ 2019;365:l1855
- Alice R Carter, graduate student12,
- Dipender Gill, clinical research training fellow3,
- Neil M Davies, senior research fellow12,
- Amy E Taylor, research fellow24,
- Taavi Tillmann, clinical lecturer5,
- Julien Vaucher, senior clinical lecturer67,
- Robyn E Wootton, research associate148,
- Marcus R Munafò, professor1489,
- Gibran Hemani, senior research fellow12,
- Rainer Malik, postdoctoral fellow10,
- Sudha Seshadri, professor1114,
- Daniel Woo, professor15,
- Stephen Burgess, statistician11617,
- George Davey Smith, professor124,
- Michael V Holmes, associate professor11820,
- Ioanna Tzoulaki, reader32122,
- Laura D Howe, reader12,
- Abbas Dehghan, reader321
- 1MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
- 2Population Health Sciences, Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK
- 3Department of Biostatistics and Epidemiology, School of Public Health, Imperial College London, London, UK
- 4National Institute for Health Research Biomedical Research Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol, Bristol, UK
- 5Institute for Global Health, University College London, London, UK
- 6Lausanne University Hospital, Lausanne, Switzerland
- 7Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
- 8School of Experimental Psychology, University of Bristol, Bristol, UK
- 9UK Centre for Tobacco and Alcohol Studies, School of Psychological Science, University of Bristol, Bristol, UK
- 10Institute for Stroke and Dementia Research, University Hospital of Ludwig-Maximilians University, Munich, Germany
- 11Glenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases, University of Texas Health Sciences Centre, San Antonio, TX, USA
- 12University of Texas Health Sciences Center, San Antonio, TX, USA
- 13Department of Neurology, Boston University School of Medicine, Boston, MA, USA
- 14The Framingham Heart Study, Framingham, MA, USA
- 15Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- 16MRC Biostatistics Unit, University of Cambridge, Cambridge, UK
- 17Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
- 18MRC Population Health Research Unit at the University of Oxford, Oxford, UK
- 19Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK
- 20National Institute for Health Research, Oxford Biomedical Research Centre, Oxford University Hospital, Oxford, UK
- 21MRC-PHE Centre for Environment, School of Public Health, Imperial College London, London, UK
- 22Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece
- Correspondence to: A Carter @alicerosecarter on Twitter) (or
- Accepted 25 March 2019
Objectives To investigate the role of body mass index (BMI), systolic blood pressure, and smoking behaviour in explaining the effect of education on the risk of cardiovascular disease outcomes.
Design Mendelian randomisation study.
Setting UK Biobank and international genome-wide association study data.
Participants Predominantly participants of European ancestry.
Exposure Educational attainment, BMI, systolic blood pressure, and smoking behaviour in observational analysis, and randomly allocated genetic variants to instrument these traits in mendelian randomisation.
Main outcomes measure The risk of coronary heart disease, stroke, myocardial infarction, and cardiovascular disease (all subtypes; all measured in odds ratio), and the degree to which this is mediated through BMI, systolic blood pressure, and smoking behaviour respectively.
Results Each additional standard deviation of education (3.6 years) was associated with a 13% lower risk of coronary heart disease (odds ratio 0.86, 95% confidence interval 0.84 to 0.89) in observational analysis and a 37% lower risk (0.63, 0.60 to 0.67) in mendelian randomisation analysis. As a proportion of the total risk reduction, BMI was estimated to mediate 15% (95% confidence interval 13% to 17%) and 18% (14% to 23%) in the observational and mendelian randomisation estimates, respectively. Corresponding estimates were 11% (9% to 13%) and 21% (15% to 27%) for systolic blood pressure and 19% (15% to 22%) and 34% (17% to 50%) for smoking behaviour. All three risk factors combined were estimated to mediate 42% (36% to 48%) and 36% (5% to 68%) of the effect of education on coronary heart disease in observational and mendelian randomisation analyses, respectively. Similar results were obtained when investigating the risk of stroke, myocardial infarction, and cardiovascular disease.
Conclusions BMI, systolic blood pressure, and smoking behaviour mediate a substantial proportion of the protective effect of education on the risk of cardiovascular outcomes and intervening on these would lead to reductions in cases of cardiovascular disease attributable to lower levels of education. However, more than half of the protective effect of education remains unexplained and requires further investigation.
Contributors: ARC and DG contributed equally to this project and are joint first authors. AD and LDH contributed equally to this project and are joint senior authors. ARC and DG devised the project, analysed and cleaned the data, interpreted results, wrote and revised the manuscript. ARC primarily carried out analyses using the UK Biobank. DG primarily carried out two-sample mendelian randomisation analyses. AET, NMD, TT, JV, SB, GDS, MVH, IT, LDH, and AD devised the project, interpreted the results, and revised the manuscript. TT, JV, GH, SB, and GDS contributed to the design of the project and critically revised the manuscript. REW, MRM, RM, SS, and DW provided data, and critically reviewed and revised the manuscript. All authors had full access to the data in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis. ARC and DG are the guarantors. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.
Funding: No funding body has influenced data collection, analysis or its interpretations. This work was carried out using the computational facilities of the Advanced Computing Research Centre and the Research Data Storage Facility of the University of Bristol. This research was conducted using the UK Biobank Resource using application 10953. ARC is funded by an MRC PhD stipend at the MRC IEU, University of Bristol (MC_UU_00011/1). ARC, NMD, REW, MRM, GH, GDS, and LDH work in a unit that receives core funding from the MRC and University of Bristol (MC_UU_00011/1/MC_UU_00011/7). DG is funded by the Wellcome 4i Clinical PhD Programme at Imperial College London. The Economics and Social Research Council (ESRC) support NMD via a Future Research Leaders grant (ES/N000757/1). AET, REW, MRM and GDS are supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at University Hospitals Bristol NHS Foundation and the University of Bristol. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. TT is funded by an NIHR Academic Clinical Lectureship. This work was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (contracts N01-HC-25195 and HHSN268201500001I) and by grants from the National Institute on Ageing: R01AG033193, U01AG049505, U01AG058589, U01AG52409, R01AG054076 (SS). SS was also supported by additional grants from the National Institute on Ageing (R01AG049607, R01AG033040, RFAG1059421, RF1AG061872) and the National Institute of Neurological Disorders and Stroke (R01-NS017950, NS100605). The content is solely the responsibility of the authors and does not necessarily represent the official views of the US National Institutes of Health. DW acknowledges NIH Funding (NS036695 and NS030678). MVH works in a unit that receives funding from the UK Medical Research Council and is supported by a British Heart Foundation Intermediate Clinical Research Fellowship (FS/18/23/33512) and the National Institute for Health Research Oxford Biomedical Research Centre. LDH is funded by a Career Development Award from the UK Medical Research Council (MR/M020894/1).
Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf. ARC, DG, TT, JV, REW, GH, RM, SS, SB, GDS, MVH, IT, and AD declare no support from any organisation for the submitted work; 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. MRM reports grants from Pfizer and non-financial support from GlaxoSmithKline, outside the submitted work. NMD reports grants from ESRC, grants from MRC, during the conduct of the study; grants from GRAND/Pfizer for unrelated research, outside the submitted work. AET reports grants from Pfizer, outside the submitted work. LDH reports grants from MRC, during the conduct of the study. DW reports grants from NIH, during the conduct of the study.
Ethical approval: Not required. Project approval was obtained from the UK Biobank (study ID: 10953) and data will be returned to them for archiving.
Data sharing: Statistical code is available on request from the corresponding author at email@example.com. All summary statistics for two-sample mendelian randomisation are available online from each genome-wide association study consortia.
The manuscript's guarantors (ARC and DG) affirm that the 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 originally planned have been explained.
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