Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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Nature Publishing Group
2018
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| _version_ | 1797095311474163712 |
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| author | Tin, A Li, Y Brody, J Nutile, T Chu, A Huffman, J Yang, Q Chen, M 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, A Kraaij, R Amin, N Van Rooij, J Kutalik, Z Dehghan, A McKnight, B Van Duijn, C Morrison, A Psaty, B Boerwinkle, E Fox, C Woodward, O Köttgen, A |
| author_facet | Tin, A Li, Y Brody, J Nutile, T Chu, A Huffman, J Yang, Q Chen, M 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, A Kraaij, R Amin, N Van Rooij, J Kutalik, Z Dehghan, A McKnight, B Van Duijn, C Morrison, A Psaty, B Boerwinkle, E Fox, C Woodward, O Köttgen, A |
| author_sort | Tin, A |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T04:26:04Z |
| format | Journal article |
| id | oxford-uuid:ccaa465e-0214-401b-b09b-8bf6350b1ba1 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T04:26:04Z |
| publishDate | 2018 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | oxford-uuid:ccaa465e-0214-401b-b09b-8bf6350b1ba12022-03-27T07:23:54ZLarge-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levelsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:ccaa465e-0214-401b-b09b-8bf6350b1ba1EnglishSymplectic Elements at OxfordNature Publishing Group2018Tin, ALi, YBrody, JNutile, TChu, AHuffman, JYang, QChen, MRobinson-Cohen, CMacé, ALiu, JDemirkan, ASorice, RSedaghat, SSwen, MYu, BGhasemi, STeumer, AVollenweider, PCiullo, MLi, MUitterlinden, AKraaij, RAmin, NVan Rooij, JKutalik, ZDehghan, AMcKnight, BVan Duijn, CMorrison, APsaty, BBoerwinkle, EFox, CWoodward, OKöttgen, AElevated 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. |
| spellingShingle | Tin, A Li, Y Brody, J Nutile, T Chu, A Huffman, J Yang, Q Chen, M 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, A Kraaij, R Amin, N Van Rooij, J Kutalik, Z Dehghan, A McKnight, B Van Duijn, C Morrison, A Psaty, B Boerwinkle, E Fox, C Woodward, O Köttgen, A Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels |
| title | Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels |
| title_full | Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels |
| title_fullStr | Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels |
| title_full_unstemmed | Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels |
| title_short | Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels |
| title_sort | large scale whole exome sequencing association studies identify rare functional variants influencing serum urate levels |
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