Mapping of the UGT1A locus identifies an uncommon coding variant that affects mRNA expression and protects from bladder cancer

Wei Tang; Yi Ping Fu; Jonine D. Figueroa; Núria Malats; Montserrat Garcia-closas; Nilanjan Chatterjee; Manolis Kogevinas; Dalsu Baris; Michael Thun; Jennifer L. Hall; Immaculata De vivo; Demetrius Albanes; Patricia Porter-gill; Mark P. Purdue; Laurie Burdett; Luyang Liu; Amy Hutchinson; Timothy Myers; Adonina Tard́n; Consol Serra; Alfredo Carrato; Reina Garcia-closas; Josep Lloreta; Alison Johnson; Molly Schwenn; Margaret R. Karagas; Alan Schned; Amanda Black; Eric J. Jacobs; W. Ryan Diver; Susan M. Gapstur; Jarmo Virtamo; David J. Hunter; Joseph F. Fraumeni; Stephen J. Chanock; Debra T. Silverman; Nathaniel Rothman; Ludmila Prokunina-Olsson

doi:10.1093/hmg/ddr619

Mapping of the UGT1A locus identifies an uncommon coding variant that affects mRNA expression and protects from bladder cancer

Wei Tang, Yi Ping Fu, Jonine D. Figueroa, Núria Malats, Montserrat Garcia-closas, Nilanjan Chatterjee, Manolis Kogevinas, Dalsu Baris, Michael Thun, Jennifer L. Hall, Immaculata De vivo, Demetrius Albanes, Patricia Porter-gill, Mark P. Purdue, Laurie Burdett, Luyang Liu, Amy Hutchinson, Timothy Myers, Adonina Tard́n, Consol SerraAlfredo Carrato, Reina Garcia-closas, Josep Lloreta, Alison Johnson, Molly Schwenn, Margaret R. Karagas, Alan Schned, Amanda Black, Eric J. Jacobs, W. Ryan Diver, Susan M. Gapstur, Jarmo Virtamo, David J. Hunter, Joseph F. Fraumeni, Stephen J. Chanock, Debra T. Silverman, Nathaniel Rothman, Ludmila Prokunina-Olsson

Medicine - Cardiology Division

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64 Scopus citations

Abstract

A recent genome-wide association study of bladder cancer identified the UGT1A gene cluster on chromosome 2q37.1 as a novel susceptibility locus. The UGT1A cluster encodes a family of UDP-glucuronosyltransferases (UGTs), which facilitate cellular detoxification and removal of aromatic amines. Bioactivated forms of aromatic amines found in tobacco smoke and industrial chemicals are the main risk factors for bladder cancer. The association within the UGT1A locus was detected by a single nucleotide polymorphism (SNP) rs11892031. Now, we performed detailed resequencing, imputation and genotyping in this region. We clarified the original genetic association detected by rs11892031 and identified an uncommon SNP rs17863783 that explained and strengthened the association in this region (allele frequency 0.014 in 4035 cases and 0.025 in 5284 controls, OR = 0.55, 95%CI = 0.44-0.69, P = 3.3 × 10 ^-7). Rs17863783 is a synonymous coding variant Val209Val within the functional UGT1A6.1 splicing form, strongly expressed in the liver, kidney and bladder. We found the protective T allele of rs17863783 to be associated with increased mRNA expression of UGT1A6.1 in in-vitro exontrap assays and in human liver tissue samples. We suggest that rs17863783 may protect from bladder cancer by increasing the removal of carcinogens from bladder epithelium by the UGT1A6.1 protein. Our study shows an example of genetic and functional role of an uncommon protective genetic variant in a complex human disease, such as bladder cancer. Published by Oxford University Press 2012.

Original language	English (US)
Article number	ddr619
Pages (from-to)	1918-1930
Number of pages	13
Journal	Human molecular genetics
Volume	21
Issue number	8
DOIs	https://doi.org/10.1093/hmg/ddr619
State	Published - Apr 2012

Bibliographical note

Funding Information:
This project has been funded in part with federal funds from the National Cancer, Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Funding Information:
Support for individual studies that participated in the effort is as follows: SBCS (D.T.S.)—Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics and intramural, contract number NCI N02-CP-11015. FIS/Spain 98/ 1274, FIS/Spain 00/0745, PI061614 and G03/174, Fundació Marató TV3, Red Temática Investigación Cooperativa en Cáncer (RTICC), Consolíder ONCOBIO, EU-FP7-201663; and RO1-CA089715 and CA34627. NEBCS (D.T.S.)—Intramural research program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics and intramural, contract number NCI N02-CP-01037, PLCO (M.P.P.)—The NIH Genes, Environment and Health Initiative (GEI) partly funded, DNA extraction and statistical analyses (HG-06-033-NCI-01 and RO1HL091172-01), genotyping at the Johns Hopkins University Center for Inherited Disease Research (U01HG004438 and NIH HHSN268200782096C) and study coordination at the GENEVA (N.C.)—The NIH Genes, Environment and Health Initiative [GEI] partly funded DNA extraction and statistical analyses (HG-06-033-NCI-01 and RO1HL091172-01), genotyping at the Johns Hopkins University Center for Inherited Disease Research (U01HG004438 and NIH HHSN268200782096C) and study coordination at the GENEVA Coordination Center (U01 HG004446) for EAGLE and part of PLCO studies. Genotyping for the remaining part of PLCO and all ATBC and CPS-II samples were supported by the Intramural Research Program of the National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics. The PLCO is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, ATBC (D.A.)—This research was supported in part by the Intramural Research Program of the NIH and the National Cancer Institute. Additionally, this research was supported by US Public Health Service contracts N01-CN-45165, N01-RC-45035 and N01-RC-37004 from the National Cancer Institute, Department of Health and Human Services. NHS & HPFS (I.D.V.)—CA055075 and CA087969.

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Tang, W., Fu, Y. P., Figueroa, J. D., Malats, N., Garcia-closas, M., Chatterjee, N., Kogevinas, M., Baris, D., Thun, M., Hall, J. L., De vivo, I., Albanes, D., Porter-gill, P., Purdue, M. P., Burdett, L., Liu, L., Hutchinson, A., Myers, T., Tard́n, A., ... Prokunina-Olsson, L. (2012). Mapping of the UGT1A locus identifies an uncommon coding variant that affects mRNA expression and protects from bladder cancer. Human molecular genetics, 21(8), 1918-1930. Article ddr619. https://doi.org/10.1093/hmg/ddr619

Tang, W, Fu, YP, Figueroa, JD, Malats, N, Garcia-closas, M, Chatterjee, N, Kogevinas, M, Baris, D, Thun, M, Hall, JL, De vivo, I, Albanes, D, Porter-gill, P, Purdue, MP, Burdett, L, Liu, L, Hutchinson, A, Myers, T, Tard́n, A, Serra, C, Carrato, A, Garcia-closas, R, Lloreta, J, Johnson, A, Schwenn, M, Karagas, MR, Schned, A, Black, A, Jacobs, EJ, Diver, WR, Gapstur, SM, Virtamo, J, Hunter, DJ, Fraumeni, JF, Chanock, SJ, Silverman, DT, Rothman, N & Prokunina-Olsson, L 2012, 'Mapping of the UGT1A locus identifies an uncommon coding variant that affects mRNA expression and protects from bladder cancer', Human molecular genetics, vol. 21, no. 8, ddr619, pp. 1918-1930. https://doi.org/10.1093/hmg/ddr619

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title = "Mapping of the UGT1A locus identifies an uncommon coding variant that affects mRNA expression and protects from bladder cancer",

abstract = "A recent genome-wide association study of bladder cancer identified the UGT1A gene cluster on chromosome 2q37.1 as a novel susceptibility locus. The UGT1A cluster encodes a family of UDP-glucuronosyltransferases (UGTs), which facilitate cellular detoxification and removal of aromatic amines. Bioactivated forms of aromatic amines found in tobacco smoke and industrial chemicals are the main risk factors for bladder cancer. The association within the UGT1A locus was detected by a single nucleotide polymorphism (SNP) rs11892031. Now, we performed detailed resequencing, imputation and genotyping in this region. We clarified the original genetic association detected by rs11892031 and identified an uncommon SNP rs17863783 that explained and strengthened the association in this region (allele frequency 0.014 in 4035 cases and 0.025 in 5284 controls, OR = 0.55, 95%CI = 0.44-0.69, P = 3.3 × 10 -7). Rs17863783 is a synonymous coding variant Val209Val within the functional UGT1A6.1 splicing form, strongly expressed in the liver, kidney and bladder. We found the protective T allele of rs17863783 to be associated with increased mRNA expression of UGT1A6.1 in in-vitro exontrap assays and in human liver tissue samples. We suggest that rs17863783 may protect from bladder cancer by increasing the removal of carcinogens from bladder epithelium by the UGT1A6.1 protein. Our study shows an example of genetic and functional role of an uncommon protective genetic variant in a complex human disease, such as bladder cancer. Published by Oxford University Press 2012.",

author = "Wei Tang and Fu, {Yi Ping} and Figueroa, {Jonine D.} and N{\'u}ria Malats and Montserrat Garcia-closas and Nilanjan Chatterjee and Manolis Kogevinas and Dalsu Baris and Michael Thun and Hall, {Jennifer L.} and {De vivo}, Immaculata and Demetrius Albanes and Patricia Porter-gill and Purdue, {Mark P.} and Laurie Burdett and Luyang Liu and Amy Hutchinson and Timothy Myers and Adonina Tar{\'d}n and Consol Serra and Alfredo Carrato and Reina Garcia-closas and Josep Lloreta and Alison Johnson and Molly Schwenn and Karagas, {Margaret R.} and Alan Schned and Amanda Black and Jacobs, {Eric J.} and Diver, {W. Ryan} and Gapstur, {Susan M.} and Jarmo Virtamo and Hunter, {David J.} and Fraumeni, {Joseph F.} and Chanock, {Stephen J.} and Silverman, {Debra T.} and Nathaniel Rothman and Ludmila Prokunina-Olsson",

note = "Funding Information: This project has been funded in part with federal funds from the National Cancer, Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Funding Information: Support for individual studies that participated in the effort is as follows: SBCS (D.T.S.)—Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics and intramural, contract number NCI N02-CP-11015. FIS/Spain 98/ 1274, FIS/Spain 00/0745, PI061614 and G03/174, Fundaci{\'o} Marat{\'o} TV3, Red Tem{\'a}tica Investigaci{\'o}n Cooperativa en C{\'a}ncer (RTICC), Consol{\'i}der ONCOBIO, EU-FP7-201663; and RO1-CA089715 and CA34627. NEBCS (D.T.S.)—Intramural research program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics and intramural, contract number NCI N02-CP-01037, PLCO (M.P.P.)—The NIH Genes, Environment and Health Initiative (GEI) partly funded, DNA extraction and statistical analyses (HG-06-033-NCI-01 and RO1HL091172-01), genotyping at the Johns Hopkins University Center for Inherited Disease Research (U01HG004438 and NIH HHSN268200782096C) and study coordination at the GENEVA (N.C.)—The NIH Genes, Environment and Health Initiative [GEI] partly funded DNA extraction and statistical analyses (HG-06-033-NCI-01 and RO1HL091172-01), genotyping at the Johns Hopkins University Center for Inherited Disease Research (U01HG004438 and NIH HHSN268200782096C) and study coordination at the GENEVA Coordination Center (U01 HG004446) for EAGLE and part of PLCO studies. Genotyping for the remaining part of PLCO and all ATBC and CPS-II samples were supported by the Intramural Research Program of the National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics. The PLCO is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, ATBC (D.A.)—This research was supported in part by the Intramural Research Program of the NIH and the National Cancer Institute. Additionally, this research was supported by US Public Health Service contracts N01-CN-45165, N01-RC-45035 and N01-RC-37004 from the National Cancer Institute, Department of Health and Human Services. NHS & HPFS (I.D.V.)—CA055075 and CA087969.",

year = "2012",

month = apr,

doi = "10.1093/hmg/ddr619",

language = "English (US)",

volume = "21",

pages = "1918--1930",

journal = "Human molecular genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

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T1 - Mapping of the UGT1A locus identifies an uncommon coding variant that affects mRNA expression and protects from bladder cancer

AU - Tang, Wei

AU - Fu, Yi Ping

AU - Figueroa, Jonine D.

AU - Malats, Núria

AU - Garcia-closas, Montserrat

AU - Chatterjee, Nilanjan

AU - Kogevinas, Manolis

AU - Baris, Dalsu

AU - Thun, Michael

AU - Hall, Jennifer L.

AU - De vivo, Immaculata

AU - Albanes, Demetrius

AU - Porter-gill, Patricia

AU - Purdue, Mark P.

AU - Burdett, Laurie

AU - Liu, Luyang

AU - Hutchinson, Amy

AU - Myers, Timothy

AU - Tard́n, Adonina

AU - Serra, Consol

AU - Carrato, Alfredo

AU - Garcia-closas, Reina

AU - Lloreta, Josep

AU - Johnson, Alison

AU - Schwenn, Molly

AU - Karagas, Margaret R.

AU - Schned, Alan

AU - Black, Amanda

AU - Jacobs, Eric J.

AU - Diver, W. Ryan

AU - Gapstur, Susan M.

AU - Virtamo, Jarmo

AU - Hunter, David J.

AU - Fraumeni, Joseph F.

AU - Chanock, Stephen J.

AU - Silverman, Debra T.

AU - Rothman, Nathaniel

AU - Prokunina-Olsson, Ludmila

N1 - Funding Information: This project has been funded in part with federal funds from the National Cancer, Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Funding Information: Support for individual studies that participated in the effort is as follows: SBCS (D.T.S.)—Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics and intramural, contract number NCI N02-CP-11015. FIS/Spain 98/ 1274, FIS/Spain 00/0745, PI061614 and G03/174, Fundació Marató TV3, Red Temática Investigación Cooperativa en Cáncer (RTICC), Consolíder ONCOBIO, EU-FP7-201663; and RO1-CA089715 and CA34627. NEBCS (D.T.S.)—Intramural research program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics and intramural, contract number NCI N02-CP-01037, PLCO (M.P.P.)—The NIH Genes, Environment and Health Initiative (GEI) partly funded, DNA extraction and statistical analyses (HG-06-033-NCI-01 and RO1HL091172-01), genotyping at the Johns Hopkins University Center for Inherited Disease Research (U01HG004438 and NIH HHSN268200782096C) and study coordination at the GENEVA (N.C.)—The NIH Genes, Environment and Health Initiative [GEI] partly funded DNA extraction and statistical analyses (HG-06-033-NCI-01 and RO1HL091172-01), genotyping at the Johns Hopkins University Center for Inherited Disease Research (U01HG004438 and NIH HHSN268200782096C) and study coordination at the GENEVA Coordination Center (U01 HG004446) for EAGLE and part of PLCO studies. Genotyping for the remaining part of PLCO and all ATBC and CPS-II samples were supported by the Intramural Research Program of the National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics. The PLCO is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, ATBC (D.A.)—This research was supported in part by the Intramural Research Program of the NIH and the National Cancer Institute. Additionally, this research was supported by US Public Health Service contracts N01-CN-45165, N01-RC-45035 and N01-RC-37004 from the National Cancer Institute, Department of Health and Human Services. NHS & HPFS (I.D.V.)—CA055075 and CA087969.

PY - 2012/4

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AB - A recent genome-wide association study of bladder cancer identified the UGT1A gene cluster on chromosome 2q37.1 as a novel susceptibility locus. The UGT1A cluster encodes a family of UDP-glucuronosyltransferases (UGTs), which facilitate cellular detoxification and removal of aromatic amines. Bioactivated forms of aromatic amines found in tobacco smoke and industrial chemicals are the main risk factors for bladder cancer. The association within the UGT1A locus was detected by a single nucleotide polymorphism (SNP) rs11892031. Now, we performed detailed resequencing, imputation and genotyping in this region. We clarified the original genetic association detected by rs11892031 and identified an uncommon SNP rs17863783 that explained and strengthened the association in this region (allele frequency 0.014 in 4035 cases and 0.025 in 5284 controls, OR = 0.55, 95%CI = 0.44-0.69, P = 3.3 × 10 -7). Rs17863783 is a synonymous coding variant Val209Val within the functional UGT1A6.1 splicing form, strongly expressed in the liver, kidney and bladder. We found the protective T allele of rs17863783 to be associated with increased mRNA expression of UGT1A6.1 in in-vitro exontrap assays and in human liver tissue samples. We suggest that rs17863783 may protect from bladder cancer by increasing the removal of carcinogens from bladder epithelium by the UGT1A6.1 protein. Our study shows an example of genetic and functional role of an uncommon protective genetic variant in a complex human disease, such as bladder cancer. Published by Oxford University Press 2012.

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Mapping of the UGT1A locus identifies an uncommon coding variant that affects mRNA expression and protects from bladder cancer

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