Abstract
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.
Highlights
Elevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms
The genes in loci most strongly associated with serum urate levels encode for urate transporters (e.g., SLC2A9, SLC22A12, ABCG2, SLC22A11, SLC17A1) or of substrates that may be exchanged for urate (e.g., SLC16A9), as well as for regulatory proteins of urate transporters (e.g., PDZK1)[13,14]
We performed epigenome-wide association studies (EWAS) of serum urate levels with two scientific aims: first, to detect CpGs associated with serum urate levels and to investigate whether differential methylation may connect genetic risk variants of unknown molecular mechanism with serum urate levels
Summary
A complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. Such genetic co-regulation could explain the observed association of serum urate and cardiometabolic risk factors from epidemiological studies It may, at least in part, be mediated by transcription factors with major regulatory roles in both liver and kidney such as HNF1A and HNF4A3. At least in part, be mediated by transcription factors with major regulatory roles in both liver and kidney such as HNF1A and HNF4A3 Genetic variants in these transcription factors are associated with serum urate levels, and with impaired glucose handling and type 2 diabetes mellitus as well as serum cholesterol and triglyceride levels[17,18,19], suggesting that coordinated gene regulation may have joint effects on serum urate and hepatic metabolism. To evaluate whether urate-associated differentially methylated CpGs are associated with cardiometabolic risk factors, pointing toward shared regulation of the implicated genes
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