Background/Aims: Gout progresses through three disease stages: hyperuricaemia, monosodium urate crystal deposition, and innate immune response to crystals. Genome-wide association studies (GWAS) have provided insight into the molecular control of hyperuricaemia; however, less is known about progression from hyperuricaemia to gout. Our aim was to conduct the largest GWAS of gout (to date) in European people.
Methods: This study used three data-sets: EuroGout (2,242 clinically-ascertained cases; 1,302 controls), the Health Professionals Follow-Up (HPFS) and Nurses’ Health Studies (NHS) (1,038 self-ascertained cases; 1,095 controls), and UK Biobank (2,432 cases ascertained by self-report, hospital records, and/or urate-lowering therapy use; 102,989 controls). Whole-genome genotyping was performed using the Illumina CoreExome-v24 array (EuroGout), Illumina OmniExpress-v12 array (HPFS/NHS), and Affymetrix Axiom array (UK Biobank). Overlapping markers between arrays (279,939) were identified and associated with gout (adjusted for sex and age) within each data-set separately using PLINK-v1.9. An inverse-variance weighted meta-analysis was then performed per marker using meta-v4.4 within R-v3.2.3.
Results: Seven loci had genome-wide significant evidence for an association with gout (P<5x10-8) – ABCG2, GCKR, PDZK1, SLC2A9, SLC17A1-A4, SLC22A12, and TRIM46.
Conclusions: These seven loci have all been associated with serum urate levels in previous genome-wide studies. Our data emphasises the relative importance of genetic control of serum urate, compared to the genetic control of monosodium urate crystal formation or the innate immune response, in determining gout. Further analyses are required to assess whether these loci play a role in gout irrespective of their influence on serum urate levels.