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

Research output: Contribution to journalArticlepeer-review

50 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 languageEnglish (US)
Article numberddr619
Pages (from-to)1918-1930
Number of pages13
JournalHuman molecular genetics
Volume21
Issue number8
DOIs
StatePublished - Apr 2012

Bibliographical note

Funding Information:
The NCI bladder cancer GWAS and follow-up studies are supported by the intramural research program of the National Institutes of Health, National Cancer Institute.

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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