%0 Journal Article %J Nat Commun %D 2018 %T Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels. %A Tin, Adrienne %A Li, Yong %A Brody, Jennifer A %A Nutile, Teresa %A Chu, Audrey Y %A Huffman, Jennifer E %A Yang, Qiong %A Chen, Ming-Huei %A Robinson-Cohen, Cassianne %A Mace, Aurelien %A Liu, Jun %A Demirkan, Ayse %A Sorice, Rossella %A Sedaghat, Sanaz %A Swen, Melody %A Yu, Bing %A Ghasemi, Sahar %A Teumer, Alexanda %A Vollenweider, Peter %A Ciullo, Marina %A Li, Meng %A Uitterlinden, André G %A Kraaij, Robert %A Amin, Najaf %A van Rooij, Jeroen %A Kutalik, Zoltán %A Dehghan, Abbas %A McKnight, Barbara %A van Duijn, Cornelia M %A Morrison, Alanna %A Psaty, Bruce M %A Boerwinkle, Eric %A Fox, Caroline S %A Woodward, Owen M %A Köttgen, Anna %K Exome %K Genetic Predisposition to Disease %K Glucose Transport Proteins, Facilitative %K Humans %K Kidney Function Tests %K Meta-Analysis as Topic %K Organic Anion Transporters %K Organic Cation Transport Proteins %K Protein Structure, Secondary %K Uric Acid %X

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.

%B Nat Commun %V 9 %P 4228 %8 2018 10 12 %G eng %N 1 %R 10.1038/s41467-018-06620-4 %0 Journal Article %J Nat Commun %D 2021 %T Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus. %A Tin, Adrienne %A Schlosser, Pascal %A Matias-Garcia, Pamela R %A Thio, Chris H L %A Joehanes, Roby %A Liu, Hongbo %A Yu, Zhi %A Weihs, Antoine %A Hoppmann, Anselm %A Grundner-Culemann, Franziska %A Min, Josine L %A Kuhns, Victoria L Halperin %A Adeyemo, Adebowale A %A Agyemang, Charles %A Arnlöv, Johan %A Aziz, Nasir A %A Baccarelli, Andrea %A Bochud, Murielle %A Brenner, Hermann %A Bressler, Jan %A Breteler, Monique M B %A Carmeli, Cristian %A Chaker, Layal %A Coresh, Josef %A Corre, Tanguy %A Correa, Adolfo %A Cox, Simon R %A Delgado, Graciela E %A Eckardt, Kai-Uwe %A Ekici, Arif B %A Endlich, Karlhans %A Floyd, James S %A Fraszczyk, Eliza %A Gao, Xu %A Gào, Xīn %A Gelber, Allan C %A Ghanbari, Mohsen %A Ghasemi, Sahar %A Gieger, Christian %A Greenland, Philip %A Grove, Megan L %A Harris, Sarah E %A Hemani, Gibran %A Henneman, Peter %A Herder, Christian %A Horvath, Steve %A Hou, Lifang %A Hurme, Mikko A %A Hwang, Shih-Jen %A Kardia, Sharon L R %A Kasela, Silva %A Kleber, Marcus E %A Koenig, Wolfgang %A Kooner, Jaspal S %A Kronenberg, Florian %A Kuhnel, Brigitte %A Ladd-Acosta, Christine %A Lehtimäki, Terho %A Lind, Lars %A Liu, Dan %A Lloyd-Jones, Donald M %A Lorkowski, Stefan %A Lu, Ake T %A Marioni, Riccardo E %A März, Winfried %A McCartney, Daniel L %A Meeks, Karlijn A C %A Milani, Lili %A Mishra, Pashupati P %A Nauck, Matthias %A Nowak, Christoph %A Peters, Annette %A Prokisch, Holger %A Psaty, Bruce M %A Raitakari, Olli T %A Ratliff, Scott M %A Reiner, Alex P %A Schöttker, Ben %A Schwartz, Joel %A Sedaghat, Sanaz %A Smith, Jennifer A %A Sotoodehnia, Nona %A Stocker, Hannah R %A Stringhini, Silvia %A Sundström, Johan %A Swenson, Brenton R %A van Meurs, Joyce B J %A van Vliet-Ostaptchouk, Jana V %A Venema, Andrea %A Völker, Uwe %A Winkelmann, Juliane %A Wolffenbuttel, Bruce H R %A Zhao, Wei %A Zheng, Yinan %A Loh, Marie %A Snieder, Harold %A Waldenberger, Melanie %A Levy, Daniel %A Akilesh, Shreeram %A Woodward, Owen M %A Susztak, Katalin %A Teumer, Alexander %A Köttgen, Anna %K Amino Acid Transport System y+ %K Cohort Studies %K CpG Islands %K DNA Methylation %K Epigenome %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Glucose Transport Proteins, Facilitative %K Gout %K Humans %K Male %K Uric Acid %X

Elevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p < 1.1E-7) CpGs explain 11.6% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.

%B Nat Commun %V 12 %P 7173 %8 2021 12 09 %G eng %N 1 %R 10.1038/s41467-021-27198-4