Genetic studies offer the possibility to gain novel insights into the molecular mechanisms of these kidney-related traits. Our understanding of human physiology and pathophysiology of both glomerular and tubular kidney function is still limited. The treatment of gout is suboptimal resulting in recurrent gout flares 5. population and up to 10% of high risk populations 3, 4. Elevated serum urate levels, hyperuricemia, can cause gout, an excruciating disease that affects 4% of the U.S. Many genes that participate in the tubular reabsorption of urate are primarily expressed in the kidney 2. Serum urate is freely filtered by the kidney followed by a complex balance of tubular reabsorption and secretion 2. The importance of tubular kidney function is illustrated by the regulation of urate metabolism. It is essential in filtering blood and actively reabsorbing and secreting solutes, metabolites and proteins during tubular passage. The kidney has a fundamental role in whole body homeostasis 1. 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. In SLC2A9, mapping of rare variants of large effects onto the predicted protein structure reveals new residues that may affect urate binding. 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. 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). 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.
Previous GWAS identified common variants with modest effects on serum urate. Nature Communications volume 9, Article number: 4228 ( 2018)Įlevated serum urate levels can cause gout, an excruciating disease with suboptimal treatment. Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels