European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene
European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene
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DOI：
10.1093/hmg/ddr303
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发表时间：
2011-11-01
影响因子：
3.5
通讯作者：
Kiemeney, Lambertus A.
中科院分区：
文献类型：
--
作者：
Rafnar, Thorunn;Vermeulen, Sita H.;Kiemeney, Lambertus A.
欧洲和美国的三项全基因组关联研究报告了8个膀胱癌(UBC)易感基因。利用扩展的病例和对照序列和5 340 737个单核苷酸多态(SNPs)的1000个基因组序列，我们在欧洲GWAS中寻找额外的基因座。发现样本集包括来自荷兰的1631例病例和3822例对照以及来自冰岛的603例病例和37781例对照。在随访中，我们使用了来自13个欧洲和伊朗血统样本集的3790个病例和7507个对照。在发现分析的基础上，我们跟踪了尿素转运蛋白(UT)基因SLC14A中的信号。该基因座上最强的信号是内含子3的SNP，rs17674580，在整个发现和随访组的分析中达到全基因组意义：优势比=1.17，P=7.6×10(-11)。UTS的SLC14A1代码定义了KIDD血型，对于维持肾脏髓质中恒定的尿素浓度梯度以及通过这一点，肾脏浓缩尿液的能力至关重要。推测rs17674580或LD中的其他序列变异通过影响尿量间接改变了UBC的风险。如果得到证实，这将支持“尿源性接触假说”，即尿量和排尿频率会改变UBC的风险。
Three genome-wide association studies in Europe and the USA have reported eight urinary bladder cancer (UBC) susceptibility loci. Using extended case and control series and 1000 Genomes imputations of 5 340 737 single-nucleotide polymorphisms (SNPs), we searched for additional loci in the European GWAS. The discovery sample set consisted of 1631 cases and 3822 controls from the Netherlands and 603 cases and 37 781 controls from Iceland. For follow-up, we used 3790 cases and 7507 controls from 13 sample sets of European and Iranian ancestry. Based on the discovery analysis, we followed up signals in the urea transporter (UT) gene SLC14A. The strongest signal at this locus was represented by a SNP in intron 3, rs17674580, that reached genome-wide significance in the overall analysis of the discovery and follow-up groups: odds ratio = 1.17, P = 7.6 x 10(-11). SLC14A1 codes for UTs that define the Kidd blood group and are crucial for the maintenance of a constant urea concentration gradient in the renal medulla and, through this, the kidney's ability to concentrate urine. It is speculated that rs17674580, or other sequence variants in LD with it, indirectly modifies UBC risk by affecting urine production. If confirmed, this would support the 'urogenous contact hypothesis' that urine production and voiding frequency modify the risk of UBC.