Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels.

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

SUBMITTER: Tin A 

PROVIDER: S-EPMC6185909 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature