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

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Title: Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels
Authors: 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
Item Type: Journal Article
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.
Issue Date: 12-Oct-2018
Date of Acceptance: 13-Sep-2018
ISSN: 2041-1723
Publisher: Nature Research (part of Springer Nature)
Journal / Book Title: Nature Communications
Volume: 9
Issue: 1
Copyright Statement: © The Author(s) 2018. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article ’ s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article ’ s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit licenses/by/4.0/
Keywords: MD Multidisciplinary
Publication Status: Published
Conference Place: England
Article Number: ARTN 4228
Appears in Collections:Faculty of Medicine
Epidemiology, Public Health and Primary Care

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