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Association of plasma uric acid with ischaemic heart disease and blood pressure: mendelian randomisation analysis of two large cohorts

BMJ 2013; 347 doi: https://doi.org/10.1136/bmj.f4262 (Published 18 July 2013) Cite this as: BMJ 2013;347:f4262
  1. Tom M Palmer, assistant professor1,
  2. Børge G Nordestgaard, professor345,
  3. Marianne Benn, senior consultant34,
  4. Anne Tybjærg-Hansen, professor3456,
  5. George Davey Smith, professor2,
  6. Debbie A Lawlor, professor2,
  7. Nicholas J Timpson, reader2
  1. 1Division of Health Sciences, Warwick Medical School, University of Warwick, Warwick, UK
  2. 2Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Bristol BS8 2BN, UK
  3. 3Department of Clinical Biochemistry and The Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark
  4. 4Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  5. 5The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Denmark
  6. 6Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Denmark
  1. Correspondence to: N J Timpson n.j.timpson{at}bristol.ac.uk
  • Accepted 27 June 2013

Abstract

Objectives To assess the associations between both uric acid levels and hyperuricaemia, with ischaemic heart disease and blood pressure, and to explore the potentially confounding role of body mass index.

Design Mendelian randomisation analysis, using variation at specific genes (SLC2A9 (rs7442295) as an instrument for uric acid; and FTO (rs9939609), MC4R (rs17782313), and TMEM18 (rs6548238) for body mass index).

Setting Two large, prospective cohort studies in Denmark.

Participants We measured levels of uric acid and related covariables in 58 072 participants from the Copenhagen General Population Study and 10 602 from the Copenhagen City Heart Study, comprising 4890 and 2282 cases of ischaemic heart disease, respectively.

Main outcome Blood pressure and prospectively assessed ischaemic heart disease.

Results Estimates confirmed known observational associations between plasma uric acid and hyperuricaemia with risk of ischaemic heart disease and diastolic and systolic blood pressure. However, when using genotypic instruments for uric acid and hyperuricaemia, we saw no evidence for causal associations between uric acid, ischaemic heart disease, and blood pressure. We used genetic instruments to investigate body mass index as a potentially confounding factor in observational associations, and saw a causal effect on uric acid levels. Every four unit increase of body mass index saw a rise in uric acid of 0.03 mmol/L (95% confidence interval 0.02 to 0.04), and an increase in risk of hyperuricaemia of 7.5% (3.9% to 11.1%).

Conclusion By contrast with observational findings, there is no strong evidence for causal associations between uric acid and ischaemic heart disease or blood pressure. However, evidence supports a causal effect between body mass index and uric acid level and hyperuricaemia. This finding strongly suggests body mass index as a confounder in observational associations, and suggests a role for elevated body mass index or obesity in the development of uric acid related conditions.

Footnotes

  • We thank Dorthe Uldall Andersen for her excellent genotyping, and the staff and participants of the Copenhagen General Population Study and Copenhagen City Heart Study for their important contributions.

  • Contributors: NJT, GDS, and BGN conceived and coordinated the investigation. NJT and TMP wrote the manuscript. MB was responsible for the preparation of data and TMP, BGN, MB, AT-H, GDS, DAL, and NJT undertook revisions and contributed intellectually to the development of this paper.

  • Funding: NJT, DAL, and GDS work in the UK Medical Research Council Integrative Epidemiology Unit at the University of Bristol. TMP also received support from a UK Medical Research Council grant (G0601625). The Copenhagen General Population Study and Copenhagen City Heart Study are supported by the Danish Heart Foundation, Danish Medical Research Council, Copenhagen County Foundation, and Herlev Hospital, Copenhagen University Hospital. All researchers operate independently of the funding bodies noted in this disclosure.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; NJT, GDS, and DAL are supported by UK Medical Research Council funding; no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: The studies were approved by the Danish ethical committees and Herlev Hospital, Copenhagen University Hospital (100.2039/91 and 01- 144/01, Copenhagen and Frederiksberg committee).

  • Data sharing: Additional data regarding technical details, statistical code, and derivative data is available from the principal investigator at boerge.nordestgaard{at}regionh.dk. Data access for further analyses is possible through direct collaborative agreement or through locally managed access arranged through the study’s principal investigator.

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 3.0) 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/3.0/.

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