European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene

作者：Þórunn Rafnar, Sita H. H. M. Vermeulen, Patrick Sulem, Guðmar Þorleifsson, Katja K.H. Aben, Johannes Alfred Witjes, Anne J. Grotenhuis, Gerald W.C.T Verhaegh, Christina A. Hulsbergen‐van de Kaa, Søren Besenbacher, Daniel Fannar Gudbjartsson, Simon Stacey, Jūlı́us Guðmundsson, Hrefna Johannsdottir, Hjördis Bjarnason, Carlo Zanon, Hafdis Th. Helgadottir, Jon Gunnlaugur Jonasson, Laufey Tryggvadóttír, Eiríkur Jónsson, Guðmundur Geirsson, Sigfús Þór Nikulásson, Vigdís Pétursdóttir, D. Timothy Bishop, Sei Chung-Sak, Ananya Choudhury, Faye Elliott, Jennifer H. Barrett, Margaret A. Knowles, Petra J. de Verdier, Charlotta Ryk, Annika Lindblom, Péter Rudnai, Eugen Stelian Gurzau, Kvetoslava Koppová, Paolo Vineis, Silvia Polidoro, Simonetta Guarrera, Carlotta Sacerdote, Angeles Panadero, José I Sanz-Velez, Manuel Sanchez, Gabriel Valdivia, María Dolores García-Prats, Jan Georg Hengstler, Silvia Selinski, Holger Gerullis, Д Ю Овсянников, Abdolaziz Khezri, Alireza Aminsharifi, Mahyar Malekzadeh, Leonard H. van den Berg, Roel A. Ophoff, Jan Herman Veldink, Maurice Petrus Zeegers, Eliane Kellen, Jacopo Fostinelli, Daniele Andreoli, Cecilia Arici, Stefano Porru, Frank Buntinx, Abbas Ali Ghaderi, Klaus Golka, Jose Ignacio Mayordomo, Giuseppe Matullo, Rajiv Kumar, Gunnar Steineck, Anne E. Kiltie, Augustine Kong, Unnur Arna Thorsteinsdottir, Kāri Stefánsson, Lambertus A.L.M. Kiemeney · 发表于：Human Molecular Genetics · 年份：2011 · DOI：10.1093/hmg/ddr303 · 被引用次数：158 · 研究领域：Epigenetics and DNA Methylation、Genetic Associations and Epidemiology、Bladder and Urothelial Cancer Treatments

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.