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

Abstract

BackgroundIncreased 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.MethodsThis 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.ResultsCoffee 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.ConclusionCoffee 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.Electronic supplementary materialThe online version of this article (10.1186/s13075-018-1629-5) contains supplementary material, which is available to authorized users.

Identification of 22 novel loci associated with urinary biomarkers of albumin, sodium, and potassium excretion

“…29 Furthermore, another locus associated with urinary sodium, MLXIPL, has been associated with reduced serum uric acid concentrations and consequently a lower risk of gout, but also with increased coffee consumption. 30 Multiple studies have reported that increased coffee consumption is associated with reduced serum uric acid concentrations 31 and lower risk of developing gout. 32,33 This association has been attributed to several potential mechanisms including improved insulin resistance 34 and caffeine-mediated inhibition of xanthine oxidase.…”

A Network Pharmacology Exploring the Mechanism of a Chinese Medicine Pair for the Treatment of Gout

“…Gout is a kind of hyperuricemia caused by the increased synthesis or decreased excretion of uric acid due to the disorder of purine metabolism (Hutton et al 2018). When the level of uric acid in blood is too high, uric…”

“…Gout is a kind of hyperuricemia caused by the increased synthesis or decreased excretion of uric acid due to the disorder of purine metabolism (Hutton et al 2018). When the level of uric acid in blood is too high, uric acid is deposited in joints, soft tissues, cartilages and kidneys in the form of sodium salts, causing in ammatory reaction of tissues (Vazquezmellado et al 2018).…”

Coffee Consumption Reduces Gout Risk Independently of Serum Uric Acid Levels: Mendelian Randomization Analyses Across Ancestry Populations

“…Polymorphisms of ALDH therefore may affect gout independently of coffee consumption. Furthermore, Hutton et al reported that the risk alleles of GCKR and MLXIPL affect gout independently of coffee intake ( 10 ). Based on these facts, we removed rs671 ( ALDH2 ), rs1260326 ( GCKR ), and rs13234378 ( MLXIPL ) from 10 instruments and reanalyzed using the remaining seven instruments.…”