Background/Purpose: Twenty-eight genetic loci are associated with serum urate levels in Europeans. Ten are established, with a further 18 of weaker effect more recently detected. SLC2A9, ABCG2, SLC17A1 and GCKR, with stronger effect sizes, have been consistently associated with gout. Evidence for association with gout at the other 24 loci is absent, equivocal or not replicated, with one explanation likely to be non-clinical ascertainment of gout. Our aim was to test the loci with prevalent gout meeting the ACR gout classification criteria in Aotearoa New Zealand (NZ) European and Polynesian case-control sample sets.

Methods: 648 NZ European cases and 1550 controls, and 888 Polynesian (Māori and Pacific) cases and 1095 controls were genotyped. Association with gout was tested by logistic regression adjusting for age and sex, and ancestry estimate for Polynesians. Power was adequate (>0.7) to detect effects of OR>1.3.

Results: We focused on the 24 loci without consistent evidence for association with gout. Association was detected at seven loci in Europeans, one of which was the first report of association with gout (IGFR1) (Figure). In combined Polynesians association with gout was detected at three loci (SLC22A12, SFMBT1, VEGFA). Meta-analysis of Europeans and Polynesians revealed association at nine loci, two which had not previously been associated with gout (PDZK1 and MAF). In participants with higher Polynesian ancestry, there was association in an opposing direction to Europeans at PRKAG2 and HLF (Figure). In Europeans there was obvious inconsistency of gout association at four loci (GCKR, INHBC, SLC22A11, SLC16A9) that display very similar effects on urate levels.

Conclusion: We provide the first evidence for association with gout at four (IGRF1, PDZK1, MAF, HLF) serum urate loci not previously associated with gout. Understanding reasons for lack of correlation between urate and gout effect sizes will be important in understanding the etiology of urate control and risk of gout.

Reference: Kottgen et al. Nat Genet. 2013;45:145-54.

Figure Adjusted odds ratio of association of 28 serum loci with gout in NZ Europeans (yellow) and people with higher Polynesian ancestry (blue). Serum urate effect sizes taken from Kottgen et al. are shown (green triangles). * P ² 0.05, ** P ² 0.01, *** P ² 0.001, **** P ² 0.0001.