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dc.contributor.authorTin, A.
dc.contributor.authorLi, Y.
dc.contributor.authorBrody, J.A.
dc.date.accessioned2019-06-21T18:46:33Z
dc.date.available2019-06-21T18:46:33Z
dc.date.issued2018
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85054895100&doi=10.1038%2fs41467-018-06620-4&partnerID=40&md5=0306d8305dc551ed2e7a3715c2c3c337
dc.identifier.urihttp://hdl.handle.net/10713/9773
dc.description.abstractElevated 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. Copyright 2018, The Author(s).en_US
dc.description.urihttps://dx.doi.org/10.1038/s41467-018-06620-4en_US
dc.language.isoen-USen_US
dc.publisherNature Publishing Groupen_US
dc.relation.ispartofNature Communications
dc.subjectUric Aciden_US
dc.subjectGouten_US
dc.subjectrenal urateen_US
dc.subjectxomeen_US
dc.subjectGenetic Predisposition to Diseaseen_US
dc.subjectKidney Function Testsen_US
dc.titleLarge-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levelsen_US
dc.typeArticleen_US
dc.identifier.doi10.1038/s41467-018-06620-4
dc.identifier.pmid30315176


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