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. 2013 Jul 18:347:f4262.
doi: 10.1136/bmj.f4262.

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

Tom M Palmer  1 , Børge G Nordestgaard, Marianne Benn, Anne Tybjærg-Hansen, George Davey Smith, Debbie A Lawlor, Nicholas J Timpson
Affiliations

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

Tom M Palmer et al. BMJ. .

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.

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Conflict of interest statement

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@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.

Figures

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Fig 1 Directed acyclic graph for instrumental variable analysis using SLC2A9 (rs7442295) as an instrument for the effect of uric acid and hypericaemia on ischaemic heart disease and blood pressure
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Fig 2 Forest plot showing observational and instrumental variable estimates of the effect of standardised urate on ischaemic heart disease. Observational adjusted estimates adjusted for age, sex, smoking, education, and income. CGPS=Copenhagen General Population Study; CCHS=Copenhagen City Heart Study; 0.09 mmol/L change in uric acid represents one standard deviation
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Fig 3 Forest plot showing observational and instrumental variable estimates of the effect of hyperuricaemia status on ischaemic heart disease. Observational adjusted estimates adjusted for age, sex, smoking, education, and income. CGPS=Copenhagen General Population Study; CCHS=Copenhagen City Heart Study; 0.09 mmol/L change in uric acid represents one standard deviation
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Fig 4 Forest plot of observational and instrumental variable estimates of a 4 unit increase in body mass index on standardised urate converted to mmol/L. Observational adjusted estimates adjusted for age, sex, smoking, education, and income. CGPS=Copenhagen General Population Study; CCHS=Copenhagen City Heart Study
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Fig 5 Forest plot of observational and instrumental variable estimates of a 4 unit increase in body mass index on hyperuricaemia status. Observational adjusted estimates adjusted for age, sex, smoking, education, and income. CGPS=Copenhagen General Population Study; CCHS=Copenhagen City Heart Study
See this image and copyright information in PMC

Comment in

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