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Nat Commun. 2018 Oct 12;9(1):4228. doi: 10.1038/s41467-018-06620-4.

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

Author information

1
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA. atin1@jhu.edu.
2
Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, 79106, Germany.
3
Cardiovascular Health Research Unit, DoM, University of Washington, Seattle, WA, 98195, USA.
4
Institute of Genetics and Biophysics "Adriano Buzzati-Traverso" - CNR, Naples, 80131, Italy.
5
Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Framingham, MA, 01702, USA.
6
Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, MA, 01702, USA.
7
VA Boston Healthcare System, Center for Population Genomics, Jamaica Plain, MA, 02130, USA.
8
Department of Biostatistics, School of Public Health, Boston University, Boston, MA, 02118, USA.
9
Department of Nephrology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
10
Department of Computational Biology, University of Lausanne, Lausanne, 1015, Switzerland.
11
Department of Epidemiology, Erasmus Medical Center, Rotterdam, 3000 CA, Netherlands.
12
Department of Human Genetics, Leiden University Medical Center, Leiden, 2300 RA, The Netherlands.
13
IRCCS Neuromed, Pozzilli, 86077, Isernia, Italy.
14
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA.
15
UTHealth School of Public Health, Houston, Texas, 77030, USA.
16
Institute for Community Medicine, University Medicine Greifswald, Greifswald, 17475, Germany.
17
Partner site Greifswald, German Center for Cardiovascular Research (DZHK), Greifswald, 17475, Germany.
18
Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, 1011, Switzerland.
19
Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
20
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, 3000 CA, The Netherlands.
21
Institute of Social and Preventive Medicine (IUMSP), Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, 1010, Switzerland.
22
Leiden Academic Centre for Drug Research, Leiden University, Leiden, 2300 RA, Netherlands.
23
Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. owoodward@som.umaryland.edu.
24
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA. anna.koettgen@uniklinik-freiburg.de.
25
Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, 79106, Germany. anna.koettgen@uniklinik-freiburg.de.

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.

PMID:
30315176
PMCID:
PMC6185909
DOI:
10.1038/s41467-018-06620-4
[Indexed for MEDLINE]
Free PMC Article

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