Elevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p < 1.1E–7) CpGs explain 11.6% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.
Bibliographical noteFunding Information:
J. Ärnlöv has served on advisory boards for AstraZeneca and Boehringer Ingelheim, and has received lecturing fees from AstraZeneca and Novartis, all unrelated to the present project. J. Coresh has grants from NIH and is a consultant to healthy.io. J. S. Floyd has consulted for Shionogi Inc. C. Herder reports personal fees from Sanofi and Lilly and grant support from Sanofi outside the submitted work. M. E. Kleber is employed with SYNLAB Holding Deutschland GmbH. O. Woodward has grants from AstraZeneca outside the submitted work. W. Koenig reports personal fees from AstraZeneca, Novartis, Pfizer, The Medicines Company, DalCor, Kowa, Amgen, Corvidia, Daichii-Sankyo, Genentech, Novo Nordisk, Omeicos, Esperion, Berlin-Chemie, Sanofi, and Bristol-Myers Squibb and grants and non-financial support from Abbott, Roche Diagnostics, Beck-mann, and Singulex outside the submitted work. S. Lorkowski reports grants and personal fees from Akcea Therapeutics Germany, and personal fees from amedes, AMGEN, Berlin-Chemie, Boehringer Ingelheim Pharma, Daiichi Sankyo, Lilly Deutschland, MSD Sharp & Dohme, Novo Nordisk Pharma, Roche Pharma, Sanofi-Aventis, Synlab Holding Deutschland, Unilever, and Upfield, all outside the submitted work. R. E. Marioni has received payment from Illumina for presentations. W. März reports grants from Siemens Healthineers, grants and personal fees from Aegerion Pharmaceuticals, grants and personal fees from AMGEN, grants from Astrazeneca, grants and personal fees from Sanofi, grants and personal fees from Alexion Pharmaceuticals, grants and personal fees from BASF, grants and personal fees from Abbott Diagnostics, grants and personal fees from Numares AG, grants and personal fees from Berlin-Chemie, grants and personal fees from Akzea Therapeutics, grants from Bayer Vital GmbH, grants from bestbion dx GmbH, grants from Boehringer Ingelheim Pharma GmbH Co KG, grants from Immundiagnostik GmbH, grants from Merck Chemicals GmbH, grants from MSD Sharp and Dohme GmbH, grants from Novartis Pharma GmbH, grants from Olink Proteomics, other from Synlab Holding Deutschland GmbH, all outside the submitted work. B. Psaty serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. J. Sundström reports ownership in companies providing services to Itrim, Amgen, Janssen, Novo Nordisk, Eli Lilly, Boehringer, Bayer, Pfizer, and Astra-Zeneca, outside the submitted work. B. Kühnel is currently an employee of Regeneron Genetics Center. All other authors have nothing to declare.
© 2021, The Author(s).