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.
| Original language | English |
|---|---|
| Article number | 4228 |
| Journal | Nature Communications |
| Volume | 9 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Dec 1 2018 |
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ASJC Scopus subject areas
- Chemistry(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)
Cite this
Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels. / Tin, Adrienne; Li, Yong; Brody, Jennifer A.; Nutile, Teresa; Chu, Audrey Y.; Huffman, Jennifer E.; Yang, Qiong; Chen, Ming Huei; Robinson-Cohen, Cassianne; Macé, Aurélien; Liu, Jun; Demirkan, Ayşe; Sorice, Rossella; Sedaghat, Sanaz; Swen, Melody; Yu, Bing; Ghasemi, Sahar; Teumer, Alexanda; Vollenweider, Peter; Ciullo, Marina; Li, Meng; Uitterlinden, André G.; Kraaij, Robert; Amin, Najaf; van Rooij, Jeroen; Kutalik, Zoltán; Dehghan, Abbas; McKnight, Barbara; van Duijn, Cornelia M.; Morrison, Alanna; Psaty, Bruce M.; Boerwinkle, Eric; Fox, Caroline S.; Woodward, Owen M.; Köttgen, Anna.
In: Nature Communications, Vol. 9, No. 1, 4228, 01.12.2018.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels
AU - Tin, Adrienne
AU - Li, Yong
AU - Brody, Jennifer A.
AU - Nutile, Teresa
AU - Chu, Audrey Y.
AU - Huffman, Jennifer E.
AU - Yang, Qiong
AU - Chen, Ming Huei
AU - Robinson-Cohen, Cassianne
AU - Macé, Aurélien
AU - Liu, Jun
AU - Demirkan, Ayşe
AU - Sorice, Rossella
AU - Sedaghat, Sanaz
AU - Swen, Melody
AU - Yu, Bing
AU - Ghasemi, Sahar
AU - Teumer, Alexanda
AU - Vollenweider, Peter
AU - Ciullo, Marina
AU - Li, Meng
AU - Uitterlinden, André G.
AU - Kraaij, Robert
AU - Amin, Najaf
AU - van Rooij, Jeroen
AU - Kutalik, Zoltán
AU - Dehghan, Abbas
AU - McKnight, Barbara
AU - van Duijn, Cornelia M.
AU - Morrison, Alanna
AU - Psaty, Bruce M.
AU - Boerwinkle, Eric
AU - Fox, Caroline S.
AU - Woodward, Owen M.
AU - Köttgen, Anna
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-018-06620-4
DO - 10.1038/s41467-018-06620-4
M3 - Article
C2 - 30315176
AN - SCOPUS:85054895100
VL - 9
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 4228
ER -