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 Jonsson; Gudmundur 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; Anne E. Kiltie

doi:10.1093/hmg/ddr303

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, Anne E. Kiltie

The Rowett Institute of Nutrition and Health

University of Oxford

Research output: Contribution to journal › Article › peer-review

119 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 language	English
Article number	ddr303
Pages (from-to)	4268-4281
Number of pages	14
Journal	Human Molecular Genetics
Volume	20
Issue number	21
DOIs	https://doi.org/10.1093/hmg/ddr303
Publication status	Published - Nov 2011

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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., ... Kiltie, A. E. (2011). European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene. Human Molecular Genetics, 20(21), 4268-4281. Article ddr303. https://doi.org/10.1093/hmg/ddr303

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 & Kiltie, AE 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

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

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.",

author = "Thorunn Rafnar and Vermeulen, {Sita H.} and Patrick Sulem and Gudmar Thorleifsson and Aben, {Katja K.} and Witjes, {J. A.} and Grotenhuis, {Anne J.} and Verhaegh, {Gerald W.} and {van de Kaa}, {Christina A.Hulsbergen} and Soren Besenbacher and Daniel Gudbjartsson and Stacey, {Simon N.} and Julius Gudmundsson and Hrefna Johannsdottir and Hjordis Bjarnason and Carlo Zanon and Hafdis Helgadottir and Jonasson, {Jon Gunnlaugur} and Laufey Tryggvadottir and Eirikur Jonsson and Gudmundur Geirsson and Sigfus Nikulasson and Vigdis Petursdottir and Bishop, {D. Timothy} and Sei Chung-Sak and Ananya Choudhury and Faye Elliott and Barrett, {Jennifer H.} and Knowles, {Margaret A.} and {de Verdier}, {Petra J.} and Charlotta Ryk and Annika Lindblom and Peter Rudnai and Eugene Gurzau and Kvetoslava Koppova and Paolo Vineis and Silvia Polidoro and Simonetta Guarrera and Carlotta Sacerdote and Angeles Panadero and Sanz-Velez, {Jos{\'e} I.} and Manuel Sanchez and Gabriel Valdivia and Garcia-Prats, {Maria D.} and Hengstler, {Jan G.} and Silvia Selinski and Holger Gerullis and Daniel Ovsiannikov and Abdolaziz Khezri and Kiltie, {Anne E.}",

year = "2011",

month = nov,

doi = "10.1093/hmg/ddr303",

language = "English",

volume = "20",

pages = "4268--4281",

journal = "Human Molecular Genetics",

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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, Peter

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 - Kiltie, Anne E.

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N2 - 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.

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

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