03116nas a2200673 4500008004100000022001400041245012500055210006900180260001500249300000900264490000600273520115900279653001001438653003801448653004501486653001101531653002601542653002701568653003101595653003801626653003301664653001401697100001801711700001301729700002301742700001901765700001901784700002501803700001601828700002001844700003001864700001901894700001301913700001901926700002101945700002001966700001701986700001302003700001902016700002102035700002402056700001902080700001302099700002802112700001902140700001602159700002202175700002102197700001902218700002202237700002302259700002102282700002002303700002102323700002102344700002202365700001902387856003602406 2018 eng d a2041-172300aLarge-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels.0 aLargescale wholeexome sequencing association studies identify ra c2018 10 12 a42280 v93 a
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.
10aExome10aGenetic Predisposition to Disease10aGlucose Transport Proteins, Facilitative10aHumans10aKidney Function Tests10aMeta-Analysis as Topic10aOrganic Anion Transporters10aOrganic Cation Transport Proteins10aProtein Structure, Secondary10aUric Acid1 aTin, Adrienne1 aLi, Yong1 aBrody, Jennifer, A1 aNutile, Teresa1 aChu, Audrey, Y1 aHuffman, Jennifer, E1 aYang, Qiong1 aChen, Ming-Huei1 aRobinson-Cohen, Cassianne1 aMace, Aurelien1 aLiu, Jun1 aDemirkan, Ayse1 aSorice, Rossella1 aSedaghat, Sanaz1 aSwen, Melody1 aYu, Bing1 aGhasemi, Sahar1 aTeumer, Alexanda1 aVollenweider, Peter1 aCiullo, Marina1 aLi, Meng1 aUitterlinden, André, G1 aKraaij, Robert1 aAmin, Najaf1 avan Rooij, Jeroen1 aKutalik, Zoltán1 aDehghan, Abbas1 aMcKnight, Barbara1 aDuijn, Cornelia, M1 aMorrison, Alanna1 aPsaty, Bruce, M1 aBoerwinkle, Eric1 aFox, Caroline, S1 aWoodward, Owen, M1 aKöttgen, Anna uhttps://chs-nhlbi.org/node/7928