caa a22 4500 530216671 CHVBK 20190303132555.0 cr unu---uuuuu 181027e20181012xx s 000 0 eng 10.1038/s41467-018-06620-4 doi (SERVAL)BIB_EC5F1BA0E000 30315176 pmid 000447123000004 isiid Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels [Elektronische Daten] [A. Tin, Y. Li, J.A. Brody, T. Nutile, A.Y. Chu, J.E. Huffman, Q. Yang, M.H. Chen, C. Robinson-Cohen, A. Macé, J. Liu, A. Demirkan, R. Sorice, S. Sedaghat, M. Swen, B. Yu, S. Ghasemi, A. Teumer, P. Vollenweider, M. Ciullo, M. Li, A.G. Uitterlinden, R. Kraaij, N. Amin, J. van Rooij, Z. Kutalik, A. Dehghan, B. McKnight, C.M. van Duijn, A. Morrison, B.M. Psaty, E. Boerwinkle, C.S. Fox, O.M. Woodward, A. Köttgen] 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. Tin A. aut Li Y. aut Brody J.A. aut Nutile T. aut Chu A.Y. aut Huffman J.E. aut Yang Q. aut Chen M.H. aut Robinson-Cohen C. aut Macé A. aut Liu J. aut Demirkan A. aut Sorice R. aut Sedaghat S. aut Swen M. aut Yu B. aut Ghasemi S. aut Teumer A. aut Vollenweider P. aut Ciullo M. aut Li M. aut Uitterlinden A.G. aut Kraaij R. aut Amin N. aut van Rooij J. aut Kutalik Z. aut Dehghan A. aut McKnight B. aut van Duijn C.M. aut Morrison A. aut Psaty B.M. aut Boerwinkle E. aut Fox C.S. aut Woodward O.M. aut Köttgen A. aut Nature communications 9/1(2018-10-12), 4228 9:1<4228 2018 9 1 article serval SERVAL 700 1- Tin A. aut SERVAL 700 1- Li Y. aut SERVAL 700 1- Brody J.A. aut SERVAL 700 1- Nutile T. aut SERVAL 700 1- Chu A.Y. aut SERVAL 700 1- Huffman J.E. aut SERVAL 700 1- Yang Q. aut SERVAL 700 1- Chen M.H. aut SERVAL 700 1- Robinson-Cohen C. aut SERVAL 700 1- Macé A. aut SERVAL 700 1- Liu J. aut SERVAL 700 1- Demirkan A. aut SERVAL 700 1- Sorice R. aut SERVAL 700 1- Sedaghat S. aut SERVAL 700 1- Swen M. aut SERVAL 700 1- Yu B. aut SERVAL 700 1- Ghasemi S. aut SERVAL 700 1- Teumer A. aut SERVAL 700 1- Vollenweider P. aut SERVAL 700 1- Ciullo M. aut SERVAL 700 1- Li M. aut SERVAL 700 1- Uitterlinden A.G. aut SERVAL 700 1- Kraaij R. aut SERVAL 700 1- Amin N. aut SERVAL 700 1- van Rooij J. aut SERVAL 700 1- Kutalik Z. aut SERVAL 700 1- Dehghan A. aut SERVAL 700 1- McKnight B. aut SERVAL 700 1- van Duijn C.M. aut SERVAL 700 1- Morrison A. aut SERVAL 700 1- Psaty B.M. aut SERVAL 700 1- Boerwinkle E. aut SERVAL 700 1- Fox C.S. aut SERVAL 700 1- Woodward O.M. aut SERVAL 700 1- Köttgen A. aut SERVAL 773 0- Nature communications 9/1(2018-10-12), 4228 9:1<4228 2018 9 BK010053 XK010053 XK010000 SERVAL SERVAL SERVAL article