Substantial anti-gout effect conferred by common and rare dysfunctional variants of URAT1/SLC22A12.

OBJECTIVES: Gout, caused by chronic elevation of serum uric acid levels, is the commonest form of inflammatory arthritis. The causative effect of common and rare variants of ATP-binding cassette transporter G2 (ABCG2/BCRP) on gout risk has been studied, but, little attention has been paid to the effect of common (rs121907892, p. W258X) and rare variants of urate transporter 1 (URAT1/SLC22A12) on gout, despite dysfunctional variants of URAT1 having been identified as pathophysiological causes of renal hypouricemia.

METHODS: To address this important but overlooked issue, we investigated the effects of these URAT1 variants on gout susceptibility, using targeted exon sequencing on 480 clinically-defined gout cases and 480 controls of Japanese male in combination with a series of functional analyses of newly-identified URAT1 variants.

RESULTS: Our results show that both common and rare dysfunctional variants of URAT1 markedly decrease the risk of gout (OR 0.0338, reciprocal OR 29.6, p = 7.66 × 1 0 -8). Interestingly, we also found that the URAT1-related protective effect on gout eclipsed the ABCG2-related causative effect (OR 2.30 - 3.32). Our findings reveal only one dysfunctional variant of URAT1 to have a substantial anti-gout effect, even in the presence of causative variants of ABCG2, a "gout gene".

CONCLUSION: Our findings provide a better understanding of gout/hyperuricemia and its aetiology that is highly relevant to personalized health care. The substantial anti-gout effect of common and rare variants of URAT1 identified in the present study support the genetic concept of a 'Common Disease, Multiple Common and Rare Variant' model.