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A Mendelian Randomization Study of Circulating Uric Acid and Type 2 Diabetes.

ABSTRACT: We aimed to investigate the causal effect of circulating uric acid concentrations on type 2 diabetes risk. A Mendelian randomization study was performed using a genetic score with 24 uric acid-associated loci. We used data of the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study, comprising 24,265 individuals of European ancestry from eight European countries. During a mean (SD) follow-up of 10 (4) years, 10,576 verified incident case subjects with type 2 diabetes were ascertained. Higher uric acid was associated with a higher diabetes risk after adjustment for confounders, with a hazard ratio (HR) of 1.20 (95% CI 1.11, 1.30) per 59.48 µmol/L (1 mg/dL) uric acid. The genetic score raised uric acid by 17 µmol/L (95% CI 15, 18) per SD increase and explained 4% of uric acid variation. By using the genetic score to estimate the unconfounded effect, we found that a 59.48 µmol/L higher uric acid concentration did not have a causal effect on diabetes (HR 1.01 [95% CI 0.87, 1.16]). Including data from the Diabetes Genetics Replication And Meta-analysis (DIAGRAM) consortium, increasing our dataset to 41,508 case subjects with diabetes, the summary odds ratio estimate was 0.99 (95% CI 0.92, 1.06). In conclusion, our study does not support a causal effect of circulating uric acid on diabetes risk. Uric acid-lowering therapies may therefore not be beneficial in reducing diabetes risk.

SUBMITTER: Sluijs I

PROVIDER: S-EPMC6284788 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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A Mendelian Randomization Study of Circulating Uric Acid and Type 2 Diabetes.

Sluijs Ivonne I Holmes Michael V MV van der Schouw Yvonne T YT Beulens Joline W J JW Asselbergs Folkert W FW Huerta José María JM Palmer Tom M TM Arriola Larraitz L Balkau Beverley B Barricarte Aurelio A Boeing Heiner H Clavel-Chapelon Françoise F Fagherazzi Guy G Franks Paul W PW Gavrila Diana D Kaaks Rudolf R Khaw Kay Tee KT Kühn Tilman T Molina-Montes Esther E Mortensen Lotte Maxild LM Nilsson Peter M PM Overvad Kim K Palli Domenico D Panico Salvatore S Quirós J Ramón JR Rolandsson Olov O Sacerdote Carlotta C Sala Núria N Schmidt Julie A JA Scott Robert A RA Sieri Sabina S Slimani Nadia N Spijkerman Annemieke M W AM Tjonneland Anne A Travis Ruth C RC Tumino Rosario R van der A Daphne L DL Sharp Stephen J SJ Forouhi Nita G NG Langenberg Claudia C Riboli Elio E Wareham Nicholas J NJ

Diabetes 20150427 8

We aimed to investigate the causal effect of circulating uric acid concentrations on type 2 diabetes risk. A Mendelian randomization study was performed using a genetic score with 24 uric acid-associated loci. We used data of the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study, comprising 24,265 individuals of European ancestry from eight European countries. During a mean (SD) follow-up of 10 (4) years, 10,576 verified incident case subjects with ty ...[more]

PMID: 25918230

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Project description:AimsSerum uric acid (SUA) levels have been previously linked to a higher risk of cardiovascular disease (CVD) in individuals with type 2 diabetes (T2D) according to various observational studies. However, whether this association is causally linked or simply influenced by confounding factors is unclear. Therefore, this study utilized Mendelian randomization (MR) analysis to explore the causality between SUA levels and the risk of CVD in individuals with T2D.MethodsOur study cohort consisted of 5723 participants who were diagnosed with T2D in the National Health and Nutrition Examination Survey (NHANES) from 1999-2018. The study assessed the association between SUA levels and the risk of CVD using a multivariable logistic regression model. To further examine causality between SUA levels and CVD, a two-sample MR study was conducted utilizing genetic data from genome-wide association studies (GWAS) involving over 140,000 individuals. The main MR analysis employed the inverse-variance-weighted (IVW) method. Additionally, several sensitivity analyses were performed to evaluate the robustness and pleiotropy of the results.ResultsIn the cross-sectional study, after multivariable adjustment, participants with SUA levels >6.7 mg/dL exhibited odds ratios (ORs) of 1.51 (95% CI: 1.01-2.26, p=0.049) for heart failure, 1.02 (95% CI: 0.69-1.50, p=0.937) for coronary heart disease, 1.36 (95% CI: 0.78-2.38, p=0.285) for angina, and 1.22 (95% CI: 0.80-1.85, p=0.355) for myocardial infarction when compared to participants with SUA levels ≤ 4.6 mg/dL. However, in the IVW analysis, no causality between SUA levels and the risk of heart failure was observed (OR = 1.03, 95% CI: 0.97-1.09, p = 0.293). The secondary analysis yielded similar results (OR = 1.05, 95% CI: 0.96-1.14, p = 0.299). The sensitivity analyses further supported our primary findings.ConclusionBased on the MR study, we did not find supporting evidence for a causal association between SUA levels and the risk of heart failure.

Dataset Information

A Mendelian Randomization Study of Circulating Uric Acid and Type 2 Diabetes.

Publications

A Mendelian Randomization Study of Circulating Uric Acid and Type 2 Diabetes.

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