Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors

Abstract

Background: Elevated serum urate levels can lead to gout and are associated with cardiovascular risk factors. We performed a genome-wide association study to search for genetic susceptibility loci for serum urate and gout and investigated the causal nature of the associations of serum urate with gout and selected cardiovascular risk factors and coronary heart disease (CHD).

Methods and results: Meta-analyses of genome-wide association studies (GWAS) were performed in 5 population-based cohorts of the Cohorts for Heart and Aging Research in Genome Epidemiology consortium for serum urate and gout in 28 283 white participants. The effect of the most significant single-nucleotide polymorphism at all genome-wide significant loci on serum urate was added to create a genetic urate score. Findings were replicated in the Women's Genome Health Study (n=22 054). Single-nucleotide polymorphisms at 8 genetic loci achieved genome-wide significance with serum urate levels (P=4×10(-8) to 2×10(-242) in SLC22A11, GCKR, R3HDM2-INHBC region, RREB1, PDZK1, SLC2A9, ABCG2, and SLC17A1). Only 2 loci (SLC2A9, ABCG2) showed genome-wide significant association with gout. The genetic urate score was strongly associated with serum urate and gout (odds ratio, 12.4 per 100 μmol/L; P=3×10(-39)) but not with blood pressure, glucose, estimated glomerular filtration rate, chronic kidney disease, or CHD. The lack of association between the genetic score and the latter phenotypes also was observed in the Women's Genome Health Study.

Conclusions: The genetic urate score analysis suggested a causal relationship between serum urate and gout but did not provide evidence for one between serum urate and cardiovascular risk factors and CHD.

Figure 1. Mean urate levels and prevalence of gout across genetic urate score

Panel A: crude mean urate levels and its 95% confidence intervals for each interval of 10 μmol/l genetic urate score based on estimates from meta analysis. Panel B: crude prevalence of gout and its 95% confidence intervals for each interval of 10 μmol/l genetic urate score by pooling the counts from five studies.

Figure 2. Relationship between urate beta coefficients and gout odds ratios across all 8 loci

Gout odds ratio per minor allele (y-axis) is plotted in natural logarithmic scale against corresponding urate beta coefficient per minor allele (x-axis) for each of the 8 urate loci (each point represents a SNP, with SNP name plotted nearby). A regression line is fitted using the 8 data points. The confidence intervals for each gout odds ratio estimate and beta coeffeicent were plotted as a vertical grey bar and as a horizontal bar respectively both centered at the point.