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

• Published in: Human molecular genetics Vol. 20; no. 21; pp. 4268 - 4281
• Main Authors: Rafnar, Thorunn, Vermeulen, Sita H., Sulem, Patrick, Thorleifsson, Gudmar, Aben, Katja K., Witjes, J. Alfred, Grotenhuis, Anne J., Verhaegh, Gerald W., Hulsbergen-van de Kaa, Christina A., Besenbacher, Soren, Gudbjartsson, Daniel, Stacey, Simon N., Gudmundsson, Julius, Johannsdottir, Hrefna, Bjarnason, Hjordis, Zanon, Carlo, Helgadottir, Hafdis, Jonasson, Jon Gunnlaugur, Tryggvadottir, Laufey, Jonsson, Eirikur, Geirsson, Gudmundur, Nikulasson, Sigfus, Petursdottir, Vigdis, Bishop, D. Timothy, Chung-Sak, Sei, Choudhury, Ananya, Elliott, Faye, Barrett, Jennifer H., Knowles, Margaret A., de Verdier, Petra J., Ryk, Charlotta, Lindblom, Annika, Rudnai, Peter, Gurzau, Eugene, Koppova, Kvetoslava, Vineis, Paolo, Polidoro, Silvia, Guarrera, Simonetta, Sacerdote, Carlotta, Panadero, Angeles, Sanz-Velez, José I., Sanchez, Manuel, Valdivia, Gabriel, Garcia-Prats, Maria D., Hengstler, Jan G., Selinski, Silvia, Gerullis, Holger, Ovsiannikov, Daniel, Khezri, Abdolaziz, Aminsharifi, Alireza, Malekzadeh, Mahyar, van den Berg, Leonard H., Ophoff, Roel A., Veldink, Jan H., Zeegers, Maurice P., Kellen, Eliane, Fostinelli, Jacopo, Andreoli, Daniele, Arici, Cecilia, Porru, Stefano, Buntinx, Frank, Ghaderi, Abbas, Golka, Klaus, Mayordomo, José I., Matullo, Giuseppe, Kumar, Rajiv, Steineck, Gunnar, Kiltie, Anne E., Kong, Augustine, Thorsteinsdottir, Unnur, Stefansson, Kari, Kiemeney, Lambertus A.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.11.2011
• Subjects: Adult; Aged; Aged, 80 and over; Association Studies; Biological and medical sciences; Cancer and Oncology; Cancer och onkologi; Chromosomes, Human, Pair 18 - genetics; Disease Progression; Female; Fundamental and applied biological sciences. Psychology; Genetic Loci - genetics; Genetic Predisposition to Disease; Genetics of eukaryotes. Biological and molecular evolution; Genome-Wide Association Study; Humans; Male; Medical sciences; Medicin och hälsovetenskap; Membrane Transport Proteins - genetics; Middle Aged; Molecular and cellular biology; Nephrology. Urinary tract diseases; Polymorphism, Single Nucleotide - genetics; Reproducibility of Results; Risk Factors; Tumors of the urinary system; Urea Transporters; Urinary Bladder Neoplasms - genetics; Urinary tract. Prostate gland; White People - genetics; Young Adult; Europe; Sensitivity; Urinary system disease; Association; Genetics; Bladder disease; Identification; Urinary tract disease; Malignant tumor; European; Bladder cancer; Cancer
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/ddr303

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.