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

Thorunn Rafnar, Sita H. Vermeulen, Patrick Sulem, Gudmar Thorleifsson, Katja K. Aben, J. A. Witjes, Anne J. Grotenhuis, Gerald W. Verhaegh, Christina A.Hulsbergen van de Kaa, Soren Besenbacher, Daniel Gudbjartsson, Simon N. Stacey, Julius Gudmundsson, Hrefna Johannsdottir, Hjordis Bjarnason, Carlo Zanon, Hafdis Helgadottir, Jon Gunnlaugur Jonasson, Laufey Tryggvadottir, Eirikur JonssonGudmundur Geirsson, Sigfus Nikulasson, Vigdis Petursdottir, D. Timothy Bishop, Sei Chung-Sak, Ananya Choudhury, Faye Elliott, Jennifer H. Barrett, Margaret A. Knowles, Petra J. de Verdier, Charlotta Ryk, Annika Lindblom, Peter Rudnai, Eugene Gurzau, Kvetoslava Koppova, Paolo Vineis, Silvia Polidoro, Simonetta Guarrera, Carlotta Sacerdote, Angeles Panadero, José I. Sanz-Velez, Manuel Sanchez, Gabriel Valdivia, Maria D. Garcia-Prats, Jan G. Hengstler, Silvia Selinski, Holger Gerullis, Daniel Ovsiannikov, Abdolaziz Khezri, Alireza Aminsharifi, Mahyar Malekzadeh, Leonard H. van den Berg, Roel A. Ophoff, Jan H. Veldink, Maurice P. Zeegers, Eliane Kellen, Jacopo Fostinelli, Daniele Andreoli, Cecilia Arici, Stefano Porru, Frank Buntinx, Abbas Ghaderi, Klaus Golka, José I. Mayordomo, Giuseppe Matullo, Rajiv Kumar, Gunnar Steineck, Anne E. Kiltie, Augustine Kong, Unnur Thorsteinsdottir, Kari Stefansson, Lambertus A. Kiemeney

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Abstract

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 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 3 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.

Original languageEnglish
Article numberddr303
Pages (from-to)4268-4281
Number of pages14
JournalHuman molecular genetics
Volume20
Issue number21
DOIs
Publication statusPublished - Nov 2011

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Rafnar, T., Vermeulen, S. H., Sulem, P., Thorleifsson, G., Aben, K. K., Witjes, J. A., Grotenhuis, A. J., Verhaegh, G. W., van de Kaa, C. A. H., Besenbacher, S., Gudbjartsson, D., Stacey, S. N., Gudmundsson, J., Johannsdottir, H., Bjarnason, H., Zanon, C., Helgadottir, H., Jonasson, J. G., Tryggvadottir, L., ... Kiemeney, L. A. (2011). European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene. Human molecular genetics, 20(21), 4268-4281. [ddr303]. https://doi.org/10.1093/hmg/ddr303