Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels.

TitleLarge-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels.
Publication TypeJournal Article
Year of Publication2018
AuthorsTin, 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
JournalNature Communications
Date Published10/2018
KeywordsExome/genetics, Facilitative/chemistry, Facilitative/genetics, Facilitative/metabolism, Genetic Predisposition to Disease, Glucose Transport Proteins, Humans, Kidney Function Tests, Meta-Analysis as Topic, Organic Anion Transporters/chemistry, Organic Anion Transporters/genetics, Organic Anion Transporters/metabolism, Organic Cation Transport Proteins/chemistry, Organic Cation Transport Proteins/genetics, Organic Cation Transport Proteins/metabolism, Protein Structure, Secondary, Uric Acid/blood

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) and SLC2A9 (p = 4.5 × 10). Gout risk in rare SLC22A12 variant carriers is halved (OR = 0.5, p = 4.9 × 10). 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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Alternate JournalNat Commun
Citation Key / SERVAL ID9148
Peer reviewRefereed
PubMed ID30315176
PubMed Central IDPMC6185909
Grant ListR01 DK114091 / DK / NIDDK NIH HHS / United States


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