Archives of Toxicology

, Volume 85, Issue 6, pp 539–554 | Cite as

Genetic variants in urinary bladder cancer: collective power of the “wimp SNPs”

  • Klaus Golka
  • Silvia Selinski
  • Marie-Louise Lehmann
  • Meinolf Blaszkewicz
  • Rosemarie Marchan
  • Katja Ickstadt
  • Holger Schwender
  • Hermann M. Bolt
  • Jan G. Hengstler
Review Article


In recent years, genome-wide association studies (GWAS) have identified more than 300 validated associations between genetic variants and risk of approximately 70 common diseases. A small number of rare variants with a frequency of usually less than 1% are associated with a strongly enhanced risk, such as genetic variants of TP53, RB1, BRCA1, and BRCA2. Only a very small number of SNPs (with a frequency of more that 1% of the rare allele) have effects of a factor of two or higher. Examples include APOE4 in Alzheimer’s disease, LOXL1 in exfoliative glaucoma, and CFH in age-related macular degeneration. However, the majority of all identified SNPs have odds ratios between 1.1 and 1.5. In the case of urinary bladder cancer, all known SNPs that have been validated in sufficiently large populations are associated with odds ratios smaller than 1.5. These SNPs are located next to the following genes: MYC, TP63, PSCA, the TERT-CLPTM1L locus, FGFR3, TACC3, NAT2, CBX6, APOBEC3A, CCNE1, and UGT1A. It is likely that these moderate risk or “wimp SNPs” interact, and because of their high number, collectively have a strong influence on whether an individual will develop cancer or not. It should be considered that variants identified so far explain only approximately 5–10% of the overall inherited risk. Possibly, the remaining variance is due to an even higher number of SNPs with odds ratios smaller than 1.1. Recent studies have provided the following information: (1) The functions of genes identified as relevant for bladder cancer focus on detoxification of carcinogens, control of the cell cycle and apoptosis, as well as maintenance of DNA integrity. (2) Many novel SNPs are far away from the protein coding regions, suggesting that these SNPs are located on distant-acting transcriptional enhancers. (3) The low odds ratio of each individual bladder cancer-associated SNP is too low to justify reasonable preventive measures. However, if the recently identified SNPs interact, they may collectively result in a substantial risk that is of preventive relevance. In addition to the “novel SNPs” identified by the recent GWAS, at least 163 further variants have been reported in relation to bladder cancer, although they have not been consistently validated in independent case–control series. Moreover, given that only 60 of these 163 “old SNPs” are covered by the SNP chips used in the recent GWAS, there are in principle 103 published variants still awaiting validation or disproval. In future, besides identifying novel disease-associated rare variants by deep sequencing, it will also be important to understand how the already identified variants interact.


Genome-wide association study SNP chip comparison Bladder cancer risk Genetic variant Enzyme polymorphism Validation GSTM1 



We thank Ms. Susanne Lindemann for helpful bibliographic work.

Supplementary material

204_2011_676_MOESM1_ESM.doc (319 kb)
Supplementary material 1 (DOC 319 kb)


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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Klaus Golka
    • 1
  • Silvia Selinski
    • 1
  • Marie-Louise Lehmann
    • 1
  • Meinolf Blaszkewicz
    • 1
  • Rosemarie Marchan
    • 1
  • Katja Ickstadt
    • 2
  • Holger Schwender
    • 2
  • Hermann M. Bolt
    • 1
  • Jan G. Hengstler
    • 1
  1. 1.Leibniz Research Centre for Working Environment and Human Factors (IfADo)DortmundGermany
  2. 2.Faculty of StatisticsTU Dortmund UniversityDortmundGermany

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