Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels
Tin A., Li Y., Brody JA., Nutile T., Chu AY., Huffman JE., Yang Q., Chen M-H., Robinson-Cohen C., Macé A., Liu J., Demirkan A., Sorice R., Sedaghat S., Swen M., Yu B., Ghasemi S., Teumer A., Vollenweider P., Ciullo M., Li M., Uitterlinden AG., Kraaij R., Amin N., van Rooij J., Kutalik Z., Dehghan A., McKnight B., van Duijn CM., Morrison A., Psaty BM., Boerwinkle E., Fox CS., Woodward OM., Köttgen A.
AbstractElevated 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 transportersSLC22A12(URAT1;p = 1.3 × 10−56) andSLC2A9(p = 4.5 × 10−7). Gout risk in rareSLC22A12variant carriers is halved (OR = 0.5,p = 4.9 × 10−3). Selected rare variants inSLC22A12are 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. InSLC2A9, 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 inSLC22A12andSLC2A9for lowering serum urate and preventing gout.