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, P. 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

Research output: Contribution to journalArticle

92 Citations (Scopus)

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

Fingerprint

Neoplasm Genes
Genome-Wide Association Study
Urinary Bladder Neoplasms
Urine
Single Nucleotide Polymorphism
Genome
Kidney Medulla
Iceland
Blood Group Antigens
Netherlands
Introns
Urea
Odds Ratio
Maintenance
Kidney
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Rafnar, T., Vermeulen, S. H., Sulem, P., Thorleifsson, G., Aben, K. K., Witjes, J. A., ... 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

European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene. / Rafnar, Thorunn; Vermeulen, Sita H.; Sulem, Patrick; Thorleifsson, Gudmar; Aben, Katja K.; Witjes, J. A.; Grotenhuis, Anne J.; Verhaegh, Gerald W.; van de Kaa, Christina A Hulsbergen; 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, P.; 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.

In: Human Molecular Genetics, Vol. 20, No. 21, ddr303, 11.2011, p. 4268-4281.

Research output: Contribution to journalArticle

Rafnar, T, Vermeulen, SH, Sulem, P, Thorleifsson, G, Aben, KK, Witjes, JA, Grotenhuis, AJ, Verhaegh, GW, van de Kaa, CAH, Besenbacher, S, Gudbjartsson, D, Stacey, SN, Gudmundsson, J, Johannsdottir, H, Bjarnason, H, Zanon, C, Helgadottir, H, Jonasson, JG, Tryggvadottir, L, Jonsson, E, Geirsson, G, Nikulasson, S, Petursdottir, V, Bishop, DT, Chung-Sak, S, Choudhury, A, Elliott, F, Barrett, JH, Knowles, MA, de Verdier, PJ, Ryk, C, Lindblom, A, Rudnai, P, Gurzau, E, Koppova, K, Vineis, P, Polidoro, S, Guarrera, S, Sacerdote, C, Panadero, A, Sanz-Velez, JI, Sanchez, M, Valdivia, G, Garcia-Prats, MD, Hengstler, JG, Selinski, S, Gerullis, H, Ovsiannikov, D, Khezri, A, Aminsharifi, A, Malekzadeh, M, van den Berg, LH, Ophoff, RA, Veldink, JH, Zeegers, MP, Kellen, E, Fostinelli, J, Andreoli, D, Arici, C, Porru, S, Buntinx, F, Ghaderi, A, Golka, K, Mayordomo, JI, Matullo, G, Kumar, R, Steineck, G, Kiltie, AE, Kong, A, Thorsteinsdottir, U, Stefansson, K & Kiemeney, LA 2011, 'European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene', Human Molecular Genetics, vol. 20, no. 21, ddr303, pp. 4268-4281. https://doi.org/10.1093/hmg/ddr303
Rafnar T, Vermeulen SH, Sulem P, Thorleifsson G, Aben KK, Witjes JA et al. European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene. Human Molecular Genetics. 2011 Nov;20(21):4268-4281. ddr303. https://doi.org/10.1093/hmg/ddr303
Rafnar, Thorunn ; Vermeulen, Sita H. ; Sulem, Patrick ; Thorleifsson, Gudmar ; Aben, Katja K. ; Witjes, J. A. ; Grotenhuis, Anne J. ; Verhaegh, Gerald W. ; van de Kaa, Christina A Hulsbergen ; 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, P. ; 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. / European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene. In: Human Molecular Genetics. 2011 ; Vol. 20, No. 21. pp. 4268-4281.
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T1 - European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene

AU - Rafnar, Thorunn

AU - Vermeulen, Sita H.

AU - Sulem, Patrick

AU - Thorleifsson, Gudmar

AU - Aben, Katja K.

AU - Witjes, J. A.

AU - Grotenhuis, Anne J.

AU - Verhaegh, Gerald W.

AU - van de Kaa, Christina A Hulsbergen

AU - Besenbacher, Soren

AU - Gudbjartsson, Daniel

AU - Stacey, Simon N.

AU - Gudmundsson, Julius

AU - Johannsdottir, Hrefna

AU - Bjarnason, Hjordis

AU - Zanon, Carlo

AU - Helgadottir, Hafdis

AU - Jonasson, Jon Gunnlaugur

AU - Tryggvadottir, Laufey

AU - Jonsson, Eirikur

AU - Geirsson, Gudmundur

AU - Nikulasson, Sigfus

AU - Petursdottir, Vigdis

AU - Bishop, D. Timothy

AU - Chung-Sak, Sei

AU - Choudhury, Ananya

AU - Elliott, Faye

AU - Barrett, Jennifer H.

AU - Knowles, Margaret A.

AU - de Verdier, Petra J.

AU - Ryk, Charlotta

AU - Lindblom, Annika

AU - Rudnai, P.

AU - Gurzau, Eugene

AU - Koppova, Kvetoslava

AU - Vineis, Paolo

AU - Polidoro, Silvia

AU - Guarrera, Simonetta

AU - Sacerdote, Carlotta

AU - Panadero, Angeles

AU - Sanz-Velez, José I.

AU - Sanchez, Manuel

AU - Valdivia, Gabriel

AU - Garcia-Prats, Maria D.

AU - Hengstler, Jan G.

AU - Selinski, Silvia

AU - Gerullis, Holger

AU - Ovsiannikov, Daniel

AU - Khezri, Abdolaziz

AU - Aminsharifi, Alireza

AU - Malekzadeh, Mahyar

AU - van den Berg, Leonard H.

AU - Ophoff, Roel A.

AU - Veldink, Jan H.

AU - Zeegers, Maurice P.

AU - Kellen, Eliane

AU - Fostinelli, Jacopo

AU - Andreoli, Daniele

AU - Arici, Cecilia

AU - Porru, Stefano

AU - Buntinx, Frank

AU - Ghaderi, Abbas

AU - Golka, Klaus

AU - Mayordomo, José I.

AU - Matullo, Giuseppe

AU - Kumar, Rajiv

AU - Steineck, Gunnar

AU - Kiltie, Anne E.

AU - Kong, Augustine

AU - Thorsteinsdottir, Unnur

AU - Stefansson, Kari

AU - Kiemeney, Lambertus A.

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AB - 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.

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