Meta-analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations.
Meta-analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations.
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DOI：
10.1371/journal.pgen.1000504
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发表时间：
2009-06
期刊：
影响因子：
4.5
通讯作者：
Gieger C
中科院分区：
文献类型：
--
作者：
Kolz M;Johnson T;Sanna S;Teumer A;Vitart V;Perola M;Mangino M;Albrecht E;Wallace C;Farrall M;Johansson A;Nyholt DR;Aulchenko Y;Beckmann JS;Bergmann S;Bochud M;Brown M;Campbell H;EUROSPAN Consortium;Connell J;Dominiczak A;Homuth G;Lamina C;McCarthy MI;ENGAGE Consortium;Meitinger T;Mooser V;Munroe P;Nauck M;Peden J;Prokisch H;Salo P;Salomaa V;Samani NJ;Schlessinger D;Uda M;Völker U;Waeber G;Waterworth D;Wang-Sattler R;Wright AF;Adamski J;Whitfield JB;Gyllensten U;Wilson JF;Rudan I;Pramstaller P;Watkins H;PROCARDIS Consortium;Doering A;Wichmann HE;KORA Study;Spector TD;Peltonen L;Völzke H;Nagaraja R;Vollenweider P;Caulfield M;WTCCC;Illig T;Gieger C
血清尿酸水平升高会引起痛风，是心血管疾病和糖尿病的危险因素。为了研究血清尿酸水平的多基因基础，我们对来自14项研究的28，141名欧洲血统参与者的全基因组关联扫描进行了荟萃分析，结果发现分布在9个位点的954个SNP超过了全基因组显著性阈值，其中5个是新的。总体而言，与血清尿酸水平相关的常见变异分布在以下9个区域：SLC 2A 9（p = 5.2×10−201）、ABCG 2（p = 3.1×10−26）、SLC 17 A1（p = 3.0×10−14）、SLC 22 A11（p = 6.7×10−14）、SLC 22 A12（p = 2.0×10−9）、SLC 16 A9（p = 1.1×10−8）、GCKR（p = 1.4×10−9）、LRRC 16 A（p = 8.5×10−9）和PDZK 1附近（p = 2.7×10−9）。 分析鉴定的变体的性别差异。我们发现，SLC 2A 9中rs734553的次要等位基因在降低女性尿酸水平方面具有更大的影响，而ABCG 2中rs 2231142的次要等位基因与女性相比在男性中更强烈地升高尿酸水平。为了进一步表征鉴定的变体，我们分析了它们与一组代谢物的相关性。SLC 16 A9中的rs 12356193与DL-肉碱（p = 4.0×10−26）和丙酰-L-肉碱（p = 5.0×10−8）浓度相关，而后者又与血清UA水平相关（分别为p = 1.4×10−57和p = 8.1×10−54），在SNP、代谢物和UA水平之间形成三角形。 总之，这些关联突出了在血清尿酸水平调节中重要的其他途径，并指出了预防或治疗高尿酸血症的药物干预的新的潜在靶点。此外，这些发现强烈支持转运蛋白是调节血清尿酸水平的关键的假设。血清尿酸水平升高会引起痛风，是心血管疾病和糖尿病的危险因素。血清尿酸水平的调节受到很强的遗传控制。这项研究描述了来自14项研究的全基因组关联扫描的第一个荟萃分析，共有28，141名欧洲血统的参与者。我们发现9个不同位点的常见DNA变异与尿酸浓度相关，其中5个是新的。这些变体位于编码有机阴离子转运蛋白4（SLC 22 A11）、单羧酸转运蛋白9（SLC 16 A9）、葡萄糖激酶调节蛋白（GCKR）、Carmil（LRRC 16 A）和含PDZ结构域1（PDZK 1）附近的基因内。性别特异性的影响显示在最近确定的基因编码葡萄糖转运蛋白9（SLC 2A 9）和ATP结合盒转运蛋白（ABCG 2）的变体。基于对163种代谢物的筛选，我们显示了SLC 16 A9内鉴定的变体之一与DL-肉碱和丙酰-L-肉碱的关联。此外，DL-肉毒碱和丙酰-L-肉毒碱与血清UA水平呈强相关性，在SNP、代谢物和UA水平之间形成三角形。总之，这些关联突出了在血清尿酸水平调节中重要的途径，并指出了预防或治疗高尿酸血症的药物干预的新的潜在靶点。
Elevated serum uric acid levels cause gout and are a risk factor for cardiovascular disease and diabetes. To investigate the polygenetic basis of serum uric acid levels, we conducted a meta-analysis of genome-wide association scans from 14 studies totalling 28,141 participants of European descent, resulting in identification of 954 SNPs distributed across nine loci that exceeded the threshold of genome-wide significance, five of which are novel. Overall, the common variants associated with serum uric acid levels fall in the following nine regions: SLC2A9 (p = 5.2×10−201), ABCG2 (p = 3.1×10−26), SLC17A1 (p = 3.0×10−14), SLC22A11 (p = 6.7×10−14), SLC22A12 (p = 2.0×10−9), SLC16A9 (p = 1.1×10−8), GCKR (p = 1.4×10−9), LRRC16A (p = 8.5×10−9), and near PDZK1 (p = 2.7×10−9). Identified variants were analyzed for gender differences. We found that the minor allele for rs734553 in SLC2A9 has greater influence in lowering uric acid levels in women and the minor allele of rs2231142 in ABCG2 elevates uric acid levels more strongly in men compared to women. To further characterize the identified variants, we analyzed their association with a panel of metabolites. rs12356193 within SLC16A9 was associated with DL-carnitine (p = 4.0×10−26) and propionyl-L-carnitine (p = 5.0×10−8) concentrations, which in turn were associated with serum UA levels (p = 1.4×10−57 and p = 8.1×10−54, respectively), forming a triangle between SNP, metabolites, and UA levels. Taken together, these associations highlight additional pathways that are important in the regulation of serum uric acid levels and point toward novel potential targets for pharmacological intervention to prevent or treat hyperuricemia. In addition, these findings strongly support the hypothesis that transport proteins are key in regulating serum uric acid levels. Elevated serum uric acid levels cause gout and are a risk factor for cardiovascular disease and diabetes. The regulation of serum uric acid levels is under a strong genetic control. This study describes the first meta-analysis of genome-wide association scans from 14 studies totalling 28,141 participants of European descent. We show that common DNA variants at nine different loci are associated with uric acid concentrations, five of which are novel. These variants are located within the genes coding for organic anion transporter 4 (SLC22A11), monocarboxylic acid transporter 9 (SLC16A9), glucokinase regulatory protein (GCKR), Carmil (LRRC16A), and near PDZ domain-containing 1 (PDZK1). Gender-specific effects are shown for variants within the recently identified genes coding for glucose transporter 9 (SLC2A9) and the ATP-binding cassette transporter (ABCG2). Based on screening of 163 metabolites, we show an association of one of the identified variants within SLC16A9 with DL-carnitine and propionyl-L-carnitine. Moreover, DL-carnitine and propionyl-L-carnitine were strongly correlated with serum UA levels, forming a triangle between SNP, metabolites and UA levels. Taken together, these associations highlight pathways that are important in the regulation of serum uric acid levels and point toward novel potential targets for pharmacological intervention to prevent or treat hyperuricemia.
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Fox, Caroline S.