Association of plasma uric acid with ischaemic heart disease and blood pressure: mendelian randomisation analysis of two large cohorts
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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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Previous research has shown that genetic variants associated with BMI are associated with CRP levels and uric acid concentrations, but the reverse was not found for genetic variants which are plausible instrumental variables for CRP and uric acid.
“Previous research has shown that genetic variants associated with BMI are associated with CRP levels30,39 and associated with uric acid concentrations,40 although in both cases the reverse was not found for genetic variants which are plausible IVs for CRP and for uric acid.”
From Network Mendelian randomization: using genetic variants as instrumental variables to investigate mediation in causal pathways. (2015) · cites this paper as [40]
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Self-citation
- Authors
- Palmer, T. M., Nordestgaard, B. G., Benn, M., Tybjaerg-Hansen, A., Davey Smith, G., Lawlor, D. A., & Timpson, N. J.
- Affiliations
- University of Warwick (GB)
- University of Copenhagen (DK)
- University of Bristol (GB)
- Corresponding author
- Timpson, N. J.
- Venue
- BMJ
- Publisher
- BMJ
- Published
- 2013-07-18
- Volume
- 347
- Issue
- jul18 1
- Pages
- f4262-f4262
- ISSN
- 1756-1833 (ISSN-L)
- PMC
- PMC3715134
- OpenAlex
- W2137796179
- Cited by
- 282
- References
- 51
- Citations by year
- 2026: 8 · 2025: 11 · 2024: 18 · 2023: 13 · 2022: 14 · 2021: 22 · 2020: 19 · 2019: 20 · 2018: 20 · 2017: 32 · 2016: 30 · 2015: 37 · 2014: 31 · 2013: 7
- FWCI
- 26.53
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- BMJ (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Warwick Research Archive Portal (University of Warwick) (acceptedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Lancaster EPrints (Lancaster University) (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Bristol Research (University of Bristol) (submittedVersion)
- Funders
- Hjerteforeningen
- Sundhed og Sygdom, Det Frie Forskningsråd
- Medical Research Council
- Topics
- Health Sciences › Medicine › Nephrology › Gout, Hyperuricemia, Uric Acid
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
- Keywords
- plasma uric acid, hyperuricemia, ischemic heart disease, blood pressure, body mass index, confounding, causal inference, SLC2A9, FTO, melanocortin-4 receptor, TMEM18, obesity, genetic instruments
- MeSH terms
- Adult, Aged, Blood Pressure, Denmark, Female, Humans, Male, Middle Aged, Prospective Studies, Regression Analysis, Uric Acid, Body Mass Index, Myocardial Ischemia, Hyperuricemia, Mendelian Randomization Analysis
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