Bladder Cancer Polymorphisms in the H19 Gene and the Risk of Bladder Cancer Gerald W. Verhaegh a,b , Linda Verkleij a,c , Sita H.H.M. Vermeulen c , Martin den Heijer c,d , J. Alfred Witjes a , Lambertus A. Kiemeney a,c, * a Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands b Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands c Department of Epidemiology and Biostatistics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands d Department of Endocrinology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands european urology 54 (2008) 1118–1126 available at www.sciencedirect.com journal homepage: www.europeanurology.com Article info Article history: Accepted January 21, 2008 Published online ahead of print on February 4, 2008 Keywords: Bladder cancer H19 gene Non-coding RNA Single nucleotide polymorphisms Susceptibility Abstract Objectives: H19 is an imprinted gene coding for an oncofetal RNA that is down-regulated postnatally. Reactivation of the H19 gene has been observed in bladder tumors, and H19 expression has been associated with early recurrence of disease. In this study we examined whether sequence variants within the H19 gene are associated with the risk of developing bladder cancer. Methods: Five tagging single nucleotide polymorphisms (tagSNPs) cover- ing the H19 gene and its promoter region were selected with the use of Haploview software. One hundred and seventy-seven bladder cancer patients who were referred to our university hospital were genotyped for these tagSNPs. The genotypes were compared with those of a random sample of 204 controls of the general population. Results: A significantly decreased risk of bladder cancer was found for the rs2839698 TC genotype (odds ratio [OR], 0.60; 95% confidence interval (95%CI), 0.36–0.99), but not for CC homozygotes. The rs2839698 TC genotype was especially associated with a reduced risk of developing non–muscle-invasive disease (OR, 0.52; 95%CI, 0.28–0.94). Borderline significantly decreased risks of bladder cancer were found for the rs2107425 CT genotype (OR, 0.66; 95%CI, 0.43–1.00), but not for TT homo- zygotes or for T allele carriers of rs217727 (OR, 0.74; 95%CI, 0.51–1.06). Haplotype analysis did not result in stronger associations with bladder cancer compared with the single-locus analyses. Conclusions: An SNP polymorphism in the non–protein-encoding H19 gene is associated with a decreased risk of developing non–muscle- invasive bladder cancer. This association was found for only hetero- zygotes, not for homozygotes. # 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Department of Epidemiology and Biostatistics, internal zip 133, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Tel. +31 24 3613745; Fax: +31 24 3613505. E-mail address: B.Kiemeney@epib.umcn.nl (L.A. Kiemeney). 0302-2838/$ – see back matter # 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2008.01.060