Abstract
Elevated serum urate levels can cause gout, an excruciating disease with suboptimal treatment. Previous GWAS identified common variants with modest effects on serum urate. Here we report large-scale whole-exome sequencing association studies of serum urate and kidney function among ≤19,517 European ancestry and African-American individuals. We identify aggregate associations of low-frequency damaging variants in the urate transporters
SLC22A12
(URAT1;
p
= 1.3 × 10
−56
) and
SLC2A9
(
p
= 4.5 × 10
−7
). Gout risk in rare
SLC22A12
variant carriers is halved (OR = 0.5,
p
= 4.9 × 10
−3
). Selected rare variants in
SLC22A12
are validated in transport studies, confirming three as loss-of-function (R325W, R405C, and T467M) and illustrating the therapeutic potential of the new URAT1-blocker lesinurad. In
SLC2A9
, mapping of rare variants of large effects onto the predicted protein structure reveals new residues that may affect urate binding. These findings provide new insights into the genetic architecture of serum urate, and highlight molecular targets in
SLC22A12
and
SLC2A9
for lowering serum urate and preventing gout.
Elevated serum urate levels are a risk factor for gout. Here, Tin et al. perform whole-exome sequencing in 19,517 individuals and detect low-frequency genetic variants in urate transporter genes,
SLC22A12
and
SLC2A9
, associated with serum urate levels and confirm their damaging nature in vitro and in silico.