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

• Published in: Nature communications Vol. 9; no. 1; pp. 4228 - 11
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.10.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 49/23; 631/208/205; 631/443/272; 631/57/2283; 692/499; 82/80; Exome - genetics; Gene mapping; Genetic Predisposition to Disease; Glucose Transport Proteins, Facilitative - chemistry; Glucose Transport Proteins, Facilitative - genetics; Glucose Transport Proteins, Facilitative - metabolism; Gout; Humanities and Social Sciences; Humans; Kidney Function Tests; Kidneys; Lead poisoning; Meta-Analysis as Topic; multidisciplinary; 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; Peptide mapping; Protein structure; Protein Structure, Secondary; Proteins; Science; Science (multidisciplinary); Sequences; Uric acid; Uric Acid - blood
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-06620-4

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. Elevated serum urate levels are a risk factor for gout. Here, Tin et al. perform whole-exome sequencing in 19,517 individuals and detect low-frequency genetic variants in urate transporter genes, SLC22A12 and SLC2A9 , associated with serum urate levels and confirm their damaging nature in vitro and in silico.