deCODE Genetics, Sturlugata 8, 101 Reykjavik, Iceland.
Hum Mol Genet. 2011 Nov 1;20(21):4268-81. doi: 10.1093/hmg/ddr303. Epub 2011 Jul 12.
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 × 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.
三项在欧洲和美国开展的全基因组关联研究已经发现了八个膀胱癌(UBC)易感性位点。本研究利用扩展的病例和对照系列以及 5340737 个单核苷酸多态性(SNP)的 1000 基因组数据进行了推断,在欧洲 GWAS 中进一步寻找其他的位点。发现样本集由荷兰的 1631 例病例和 3822 例对照以及冰岛的 603 例病例和 37781 例对照组成。为了随访,我们使用了来自欧洲和伊朗血统的 13 个样本组的 3790 例病例和 7507 例对照。基于发现分析,我们对尿素转运体(UT)基因 SLC14A 中的信号进行了随访。在该基因座,最强烈的信号是位于内含子 3 中的 SNP rs17674580,在发现和随访组的总体分析中达到了全基因组显著水平:比值比=1.17,P=7.6×10(-11)。SLC14A1 编码的 UTs 定义了 Kidd 血型,对于维持肾脏髓质中尿素浓度梯度的恒定以及通过这种方式维持肾脏浓缩尿液的能力至关重要。据推测,rs17674580 或与它紧密连锁的其他序列变异间接通过影响尿液生成来改变 UBC 的风险。如果得到证实,这将支持“尿源性接触假说”,即尿液生成和排尿频率会改变 UBC 的风险。