Causal Associations of Urate With Cardiovascular Risk Factors: Two-Sample Mendelian Randomization

Thitiya Lukkunaprasit, Sasivimol Rattanasiri*, Boonsong Ongphiphadhanakul, Gareth J. McKay, John Attia, Ammarin Thakkinstian

*Corresponding author for this work

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Background: Mendelian Randomization (MR) studies show conflicting causal associations of genetically predicted serum urate with cardiovascular risk factors (i.e., hypertension, diabetes, lipid profile, and kidney function). This study aimed to robustly investigate a causal relationship between urate and cardiovascular risk factors considering single nucleotide polymorphisms (SNPs) as instrumental variables using two-sample MR and various sensitivity analyses. Methods: Data on SNP-urate associations were taken from the Global Urate Genetics Consortium and data on SNP-cardiovascular risk factor associations were taken from various consortia/UK Biobank. SNPs were selected by statistically and biologically driven approaches as instrumental variables. Various sensitivity analyses were performed using different MR methods including inverse variance weighted, MR-Egger, weighted median/mode, MR-PRESSO, and the contamination mixture method. Results: The statistically driven approach showed significant causal effects of urate on HDL-C and triglycerides using four of the six MR methods, i.e., every 1 mg/dl increase in genetically predicted urate was associated with 0.047 to 0.103 SD decrease in HDL-C and 0.034 to 0.207 SD increase in triglycerides. The biologically driven approach to selection of SNPs from ABCG2, SLC2A9, SLC17A1, SLC22A11, and SLC22A12 showed consistent causal effects of urate on HDL-C from all methods with 0.038 to 0.057 SD decrease in HDL-C per 1 mg/dl increase of urate, and no evidence of horizontal pleiotropy was detected. Conclusion: Our study suggests a significant and robust causal effect of genetically predicted urate on HDL-C. This finding may explain a small proportion (7%) of the association between increased urate and cardiovascular disease but points to urate being a novel cardiac risk factor.

Original languageEnglish
Article number687279
JournalFrontiers in Genetics
Publication statusPublished - 08 Jul 2021

Bibliographical note

Funding Information:
We thank the MRC-IEU who developed the MR-Base platform, the GUGC, the CKDgen consortium, the DIAGRAM consortium, the GIANT consortium, the GLGC, the MAGIC, and the MRC-IEU UK Biobank GWAS pipeline for providing the summary data used in this study. This work is a part of the thesis of TL in Doctor of Philosophy Program in Clinical Epidemiology, Department of Clinical Epidemiology and Biostatistics, Faculty of Medicine Ramathibodi Hospital and Faculty of Graduate Studies, Mahidol University.

Publisher Copyright:
© Copyright © 2021 Lukkunaprasit, Rattanasiri, Ongphiphadhanakul, McKay, Attia and Thakkinstian.

Copyright 2021 Elsevier B.V., All rights reserved.


  • cardiovascular risk factor
  • instrumental variable
  • Mendelian Randomization
  • urate
  • urate transporter gene

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Genetics(clinical)


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