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

  1. Author:
    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. Y.
    Hutchinson, A.
    Myers, T.
    Tardon, A.
    Serra, C.
    Carrato, A.
    Garcia-Closas, R.
    Lloreta, J.
    Johnson, A.
    Schwenn, M.
    Karagas, M. R.
    Schned, A.
    Black, A.
    Jacobs, E. J.
    Diver, W. R.
    Gapstur, S. M.
    Virtamo, J.
    Hunter, D. J.
    Fraumeni, J. F.
    Chanock, S. J.
    Silverman, D. T.
    Rothman, N.
    Prokunina-Olsson, L.

  2. Author Address

    [Prokunina-Olsson, Ludmila] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Malats, Nuria] Spanish Natl Canc Res Ctr, Madrid 28029, Spain. [Garcia-Closas, Montserrat] Inst Canc Res, Div Genet & Epidemiol, London SW7 3RP, England. [Kogevinas, Manolis] Ctr Res Environm Epidemiol CREAL, Barcelona 08003, Spain. [Kogevinas, Manolis] Municipal Inst Med Res, Barcelona 08003, Spain. [Kogevinas, Manolis; Tardon, Adonina] CIBERESP, Barcelona 08003, Spain. [Kogevinas, Manolis] Natl Sch Publ Hlth, Athens 11521, Greece. [Thun, Michael; Jacobs, Eric J.; Diver, W. Ryan; Gapstur, Susan M.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30303 USA. [Hall, Jennifer L.] Univ Minnesota, Lillehei Heart Inst, Dept Med, Minneapolis, MN 55455 USA. [De Vivo, Immaculata] Brigham & Womens Hosp, Channing Lab, Dept Med, Boston, MA 02115 USA. [Burdett, Laurie; Hutchinson, Amy; Myers, Timothy] NCI, Core Genotype Facil, SAIC Frederick Inc, Frederick, MD 21702 USA. [Tardon, Adonina] Univ Oviedo, Oviedo 33003, Spain. [Serra, Consol] Univ Pompeu Fabra, Barcelona 08002, Spain. [Carrato, Alfredo] Ramon y Cajal Univ Hosp, Madrid 28034, Spain. [Garcia-Closas, Reina] Hosp Univ Canarias, Unidad Invest, San Cristobal la Laguna 38320, Spain. [Lloreta, Josep] Univ Pompeu Fabra, Hosp Mar, IMIM, Barcelona 08003, Spain. [Johnson, Alison] Vermont Canc Registry, Burlington, VT 05401 USA. [Schwenn, Molly] Maine Canc Registry, Augusta, ME 04333 USA. [Karagas, Margaret R.] Dartmouth Med Sch, Hanover, NH 03755 USA. [Schned, Alan] Washington Univ, Sch Med, Dept Urol, St Louis, MO 63110 USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Helsinki 00271, Finland. [Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Program Mol & Genet Epidemiol, Boston, MA 02115 USA.;Prokunina-Olsson, L (reprint author), NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, 8717 Grovemont Circle, Bethesda, MD 20892 USA;prokuninal@mail.nih.gov
    1. Year: 2012
    2. Date: Apr
  2. Journal: Human Molecular Genetics
    1. 21
    2. 8
    3. Pages: 1918-1930
  4. Type of Article: Article
  5. ISSN: 0964-6906
  1. 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, 95CI 0.440.69, 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.

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  2. DOI: 10.1093/hmg/ddr619
  3. View record in Web of Science®
  4. WOS: 000302302400020

Library Notes

  1. Fiscal Year: FY2011-2012
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