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Mediation analysis to understand genetic relationships between habitual coffee intake and gout.
Arthritis Res Ther. 2018 07 05; 20(1):135.AR

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.

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Authors+Show Affiliations

Hutton J
Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, 85 Park Rd, Grafton, Auckland, New Zealand.
Fatima T
Department of Biochemistry, University of Otago, Dunedin, New Zealand.
Major TJ
Department of Biochemistry, University of Otago, Dunedin, New Zealand.
Topless R
Department of Biochemistry, University of Otago, Dunedin, New Zealand.
Stamp LK
Department of Medicine, University of Otago, Christchurch, New Zealand.
Merriman TR
Department of Biochemistry, University of Otago, Dunedin, New Zealand.
Dalbeth N
Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, 85 Park Rd, Grafton, Auckland, New Zealand. n.dalbeth@auckland.ac.nz.

MeSH

ATP Binding Cassette Transporter, Subfamily G, Member 2Adaptor Proteins, Signal TransducingAdultAgedAllelesBasic Helix-Loop-Helix Leucine Zipper Transcription FactorsCoffeeCytochrome P-450 CYP1A2Drinking BehaviorFemaleGene FrequencyGenetic Predisposition to DiseaseGoutHumansMaleMiddle AgedNeoplasm ProteinsPolymorphism, Single NucleotideUric Acid

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29976226

Citation

Hutton, Joseph, et al. "Mediation Analysis to Understand Genetic Relationships Between Habitual Coffee Intake and Gout." Arthritis Research & Therapy, vol. 20, no. 1, 2018, p. 135.
Hutton J, Fatima T, Major TJ, et al. Mediation analysis to understand genetic relationships between habitual coffee intake and gout. Arthritis Res Ther. 2018;20(1):135.
Hutton, J., Fatima, T., Major, T. J., Topless, R., Stamp, L. K., Merriman, T. R., & Dalbeth, N. (2018). Mediation analysis to understand genetic relationships between habitual coffee intake and gout. Arthritis Research & Therapy, 20(1), 135. https://doi.org/10.1186/s13075-018-1629-5
Hutton J, et al. Mediation Analysis to Understand Genetic Relationships Between Habitual Coffee Intake and Gout. Arthritis Res Ther. 2018 07 5;20(1):135. PubMed PMID: 29976226.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mediation analysis to understand genetic relationships between habitual coffee intake and gout. AU - Hutton,Joseph, AU - Fatima,Tahzeeb, AU - Major,Tanya J, AU - Topless,Ruth, AU - Stamp,Lisa K, AU - Merriman,Tony R, AU - Dalbeth,Nicola, Y1 - 2018/07/05/ PY - 2017/11/30/received PY - 2018/05/18/accepted PY - 2018/7/7/entrez PY - 2018/7/7/pubmed PY - 2019/4/23/medline KW - Coffee KW - Diet KW - Genetics KW - Gout KW - Urate SP - 135 EP - 135 JF - Arthritis research & therapy JO - Arthritis Res Ther VL - 20 IS - 1 N2 - 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. SN - 1478-6362 UR - https://www.unboundmedicine.com/medline/citation/29976226/Mediation_analysis_to_understand_genetic_relationships_between_habitual_coffee_intake_and_gout_ DB - PRIME DP - Unbound Medicine ER -