Objectives To perform a genome-wide association study (GWAS) of gout cases versus asymptomatic hyperuricaemia (AH) controls, and gout cases versus normouricaemia controls, and to generate a polygenic risk score (PRS) to determine gout-case versus AH-control status.
Methods Gout cases and AH controls (serum urate (SU) ≥6.0 mg/dL) from the UK Biobank were divided into discovery (4934 cases, 56 948 controls) and replication (2115 cases, 24 406 controls) cohorts. GWAS was conducted and PRS generated using summary statistics in discovery cohort as the base dataset and the replication cohort as the target dataset. The predictive ability of the model was evaluated. GWAS were performed to identify variants associated with gout compared with normouricaemic controls using SU <6.0 mg/dL and <7.0 mg/dL thresholds, respectively.
Results Thirteen independent single nucleotide polymorphisms (SNPs) in ABCG2, SLC2A9, SLC22A11, GCKR, MEPE, PPM1K-DT, LOC105377323 and ADH1B reached genome-wide significance and replicated as predictors of AH to gout transition. Twelve of 13 associations were novel for this transition, and rs1229984 (ADH1B) was identified as GWAS locus for gout for the first time. The best PRS model was generated from association data of 17 SNPs; and had predictive ability of 58.5% that increased to 69.2% on including demographic factors. Two novel SNPs rs760077(MTX1) and rs3800307(PRSS16) achieved GWAS significance for association with gout compared with normouricaemic controls using both SU thresholds.
Conclusion The association of urate transporters with gout supports the central role of hyperuricaemia in its pathogenesis. Larger GWAS are required to identify if variants in inflammatory pathways contribute to progression from AH to gout.
- crystal arthropathies
Data availability statement
Data may be obtained from a third party and are not publicly available. Raw data used for this study are available from the UK Biobank resource.
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Handling editor Josef S Smolen
Contributors Study concept and design: AA, GS-P, KM. Data analysis: GS-P. Manuscript preparation: GS-P, AA, KM. Manuscript revision for important intellectual content: all authors.
Funding Miss Sandoval-Plata’s work is supported by a PhD scholarship from The Mexican National Council for Science and Technology (CONACYT) (Grant number 472 298).
Competing interests Professor AA has received departmental research grants from AstraZeneca and Oxford Immunotec, speaker bureau fees from Menarini, scientific meeting support from Pfizer, author royalties from UpToDate and Springer and has consulted for Inflazome unrelated to this work.
Provenance and peer review Not commissioned; externally peer reviewed.
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