对28141名个体进行的荟萃分析确定了五个新基因座中的常见变异，这些变异会影响尿酸浓度。
Meta-analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations.
作者信息
Kolz Melanie, Johnson Toby, Sanna Serena, Teumer Alexander, Vitart Veronique, Perola Markus, Mangino Massimo, Albrecht Eva, Wallace Chris, Farrall Martin, Johansson Asa, Nyholt Dale R, Aulchenko Yurii, Beckmann Jacques S, Bergmann Sven, Bochud Murielle, Brown Morris, Campbell Harry, Connell John, Dominiczak Anna, Homuth Georg, Lamina Claudia, McCarthy Mark I, Meitinger Thomas, Mooser Vincent, Munroe Patricia, Nauck Matthias, Peden John, Prokisch Holger, Salo Perttu, Salomaa Veikko, Samani Nilesh J, Schlessinger David, Uda Manuela, Völker Uwe, Waeber Gérard, Waterworth Dawn, Wang-Sattler Rui, Wright Alan F, Adamski Jerzy, Whitfield John B, Gyllensten Ulf, Wilson James F, Rudan Igor, Pramstaller Peter, Watkins Hugh, Doering Angela, Wichmann H-Erich, Spector Tim D, Peltonen Leena, Völzke Henry, Nagaraja Ramaiah, Vollenweider Peter, Caulfield Mark, Illig Thomas, Gieger Christian
机构信息
Institute of Epidemiology, Helmholtz Zentrum München, National Research Center for Environment and Health, Neuherberg, Germany.
出版信息
PLoS Genet. 2009 Jun;5(6):e1000504. doi: 10.1371/journal.pgen.1000504. Epub 2009 Jun 5.
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 = 5.2x10(-201)), ABCG2 (p = 3.1x10(-26)), SLC17A1 (p = 3.0x10(-14)), SLC22A11 (p = 6.7x10(-14)), SLC22A12 (p = 2.0x10(-9)), SLC16A9 (p = 1.1x10(-8)), GCKR (p = 1.4x10(-9)), LRRC16A (p = 8.5x10(-9)), and near PDZK1 (p = 2.7x10(-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 = 4.0x10(-26)) and propionyl-L-carnitine (p = 5.0x10(-8)) concentrations, which in turn were associated with serum UA levels (p = 1.4x10(-57) and p = 8.1x10(-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.
血清尿酸水平升高会引发痛风，并且是心血管疾病和糖尿病的一个风险因素。为了探究血清尿酸水平的多基因基础，我们对来自14项研究的全基因组关联扫描进行了荟萃分析，这些研究共有28141名欧洲血统参与者，结果鉴定出分布在9个位点的954个单核苷酸多态性（SNP），其中5个是新发现的。总体而言，与血清尿酸水平相关的常见变异位于以下9个区域：溶质载体家族2成员9（SLC2A9，p = 5.2×10⁻²⁰¹）、ATP结合盒转运体G2（ABCG2，p = 3.1×10⁻²⁶）、溶质载体家族17成员1（SLC17A1，p = 3.0×10⁻¹⁴）、溶质载体家族22成员11（SLC22A11，p = 6.7×10⁻¹⁴）、溶质载体家族22成员12（SLC22A12，p = 2.0×10⁻⁹）、溶质载体家族16成员9（SLC16A9，p = 1.1×10⁻⁸）、葡萄糖激酶调节蛋白（GCKR，p = 1.4×10⁻⁹）、富含亮氨酸重复序列16A（LRRC16A，p = 8.5×10⁻⁹）以及靠近PDZK1蛋白（PDZK1，p = 2.7×10⁻⁹）的区域。对鉴定出的变异进行了性别差异分析。我们发现，SLC2A9基因中rs734553的次要等位基因在降低女性尿酸水平方面有更大影响，而ABCG2基因中rs2231142的次要等位基因在升高男性尿酸水平方面比女性更强。为了进一步表征鉴定出的变异，我们分析了它们与一组代谢物的关联。SLC16A9基因内的rs12356193与DL - 肉碱（p = 4.0×10⁻²⁶）和丙酰 - L - 肉碱（p = 5.0×10⁻⁸）浓度相关，而这两种代谢物又分别与血清尿酸水平相关（p分别为1.4×10⁻⁵⁷和8.1×10⁻⁵⁴），在单核苷酸多态性、代谢物和尿酸水平之间形成了一个三角关系。综上所述，这些关联突出了在血清尿酸水平调节中重要的其他途径，并指向预防或治疗高尿酸血症的药物干预新潜在靶点。此外，这些发现有力地支持了转运蛋白是调节血清尿酸水平关键因素的假说。
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