Mediation analysis to understand genetic relationships between habitual coffee intake and gout

Abstract Background Increased coffee intake is associated with reduced serum urate concentrations and lower risk of gout. Specific alleles of the GCKR, ABCG2, MLXIPL, and CYP1A2 genes have been associated with both reduced coffee intake and increased serum urate in separate genome-wide association studies (GWAS). The aim of this study was to determine whether these single nucleotide polymorphisms (SNPs) influence the risk of gout through their effects on coffee consumption. Methods This research was conducted using the UK Biobank Resource. Data were available for 130,966 European participants aged 40–69 years. Gout status and coffee intake were tested for association with four urate-associated SNPs: GCKR (rs1260326), ABCG2 (rs2231142), MLXIPL (rs1178977), and CYP1A2 (rs2472297). Multiple regression and path analysis were used to examine whether coffee consumption mediated the effect of the SNPs on gout risk. Results Coffee consumption was inversely associated with gout (multivariate adjusted odds ratio (95% confidence interval (CI)) for any coffee consumption 0.75 (0.67–0.84, P = 9 × 10−7)). There was also evidence of a dose-effect with multivariate adjusted odds ratio (95% CI) per cup consumed per day of 0.85 (0.82–0.87, P = 9 × 10−32). The urate-increasing GCKR, ABCG2, MLXIPL, and CYP1A2 alleles were associated with reduced daily coffee consumption, with the strongest associations for CYP1A2 (beta −0.30, P = 8 × 10−40), and MLXIPL (beta −0.17, P = 3 × 10−8), and weaker associations for GCKR (beta −0.07, P = 3 × 10−10) and ABCG2 (beta −0.09, P = 2 × 10−9). The urate-increasing GCKR and ABCG2 alleles were associated with gout (multivariate adjusted p < 5 × 10−8 for both), but the urate-increasing MLXIPL and CYP1A2 alleles were not. In mediation analysis, the direct effects of GCKR and ABCG2 accounted for most of the total effect on gout risk, with much smaller indirect effects mediated by coffee consumption. Conclusion Coffee consumption is inversely associated with risk of gout. Although alleles at several SNPs associate with both lower coffee consumption and higher risk of gout, these SNPs largely influence gout risk directly, rather than indirectly through effects on coffee consumption