Interaction of genetic variants towards increased cancer risk

Seddik Hammad1[*]

1Department of Forensic Medicine and Veterinary Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt

EXCLI J 2013;12:Doc625


More than 300 associations between genetic variants and common diseases have been identified in recent years (Hindorff et al., 2009[7]; Golka et al., 2009[5], 2011[6], 2012[4]; Kiemeney et al., 2010[8]; Binder et al., 2012[1]).

For cancer, most variants, also called single nucleotide polymorphism (SNP), confer only a moderate risk with odds ratios less than 1.5 (Lichtenstein et al., 2000[10]; Selinski et al., 2012[15][16], 2011[14]; Lehmann et al., 2010[9]; Ovsiannikov et al., 2012[11]; Rafnar et al., 2011[12]). Until recently, it was unknown whether interaction among the high-risk alleles of several genetic variants would lead to an increased cancer risk (Bolt, 2013[2][3]; Stewart and Marchan, 2012[17]). This was addressed in a recent study by Holger Schwender and colleagues who investigated the interaction among SNPs known to be associated with bladder cancer and risk. Their results clearly show increased overall risk, causing much excitement in the field (Schwender et al., 2012[13]).

In their work, the group from Dortmund, Germany, showed that for single SNPs, for example rs1014971 and rs9642680, the odds ratio are 1.63 and 1.48, respectively. However, combining both SNPs resulted in an increased odds ratio of 1.91 (Schwender et al., 2012[13]) - a ratio larger than the individual effects but smaller than additive (1.63 + 1.48 = 3.11). Including a third SNP also increased the odds ratio, but only by a further 0.07 (Schwender et al., 2012[13]). Using an elegant statistical approach and testing stability by bootstrapping, the authors demonstrate that stable combinations of up to three high-risk alleles result in odds ratios of up to 2.0 in non-smokers. This is clearly higher than the influence of individual high-risk alleles, but also less than the additive risk.

Although the study of Schwender (Schwender et al., 2012[13]) represents remarkable progress, one important question remains open. What would happen if more high-risk variants were added to the three-way interactions? Would there be a relevant further increase in the cancer risk? Or, would odds ratios asymptotically approach a 'natural' upper limit of 2.0 or slightly above? Schwender and colleagues could not answer this question due to the limited case numbers (1,593 urinary bladder cases and 1,760 controls). Therefore, four-way or even higher interactions could not be evaluated because the combination results were no longer stable after bootstrapping.

In conclusion, there is a definite need to bring together all data on genetic variants that is available world-wide. The increased statistical power will facilitate studies of interactions, and advance our understanding on how genetic variants interact to cause increased cancer risk.



1. Binder H, Müller T, Schwender H, Golka K, Steffens M, Hengstler JG, et al. Cluster-localized sparse logistic regression for SNP data. Stat Appl Gen Mol Biol. 2012;11(4):article 13.
2. Bolt HM. Human bladder cancer risk calucation based on genome-wide analysis of genetic variants. Arch Toxicol. 2013;87:397-9.
3. Bolt HM. Relevance of genetic disposition versus environmental exposure for cancer risk: an old controversy revisited with novel methods. EXCLI J. 2013;12:79-80.
4. Golka K, Abreu-Villaca Y, Anbari Attar R, Angeli-Greaves M, Aslam M, Basaran N, et al. Bladder cancer documentation of causes: multilingual questionnaire, 'bladder cancer doc'. Front Biosci (Elite Ed). 2012;4:2809-22.
5. Golka K, Hermes M, Selinski S, Blaszkewicz M, Bolt HM, Roth G, et al. Susceptibility to urinary bladder cancer: relevance of rs9642880[T], GSTM1 0/0 and occupational exposure. Pharmacogen Genom. 2009;19:903-6.
6. Golka K, Selinski S, Lehmann ML, Blaszkewicz M, Marchan R, Ickstadt K, et al. Genetic variants in urinary bladder cancer: collective power of the "wimp SNPs". Arch Toxicol. 2011;85:539-54.
7. Hindorff LA, Sethupathy P, Junkins HA, Ramos EM, Mehta JP, Collins FS, et al. Potential etiologic and functional implications of genome-wide association loci for human desease and traits. Proc Natl Acad Sci USA. 2009;106:9362-7.
8. Kiemeney LA, Sulem P, Besenbacher S, Vermeulen SH, Sigurdsson A, Thorleifsson G, et al. A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer. Nat Genet. 2010;42:415-9.
9. Lehmann ML, Selinski S, Blaszkewicz M, Orlich M, Ovsiannikov D, Moormann O, et al. Rs710521[A] on chromosome 3q28 close to TP63 is associated with increased urinary bladder cancer risk. Arch Toxicol. 2010;84:967-78.
10. Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, et al. Environmental and heritable factors in the causation of cancer – analyses of cohorts of twins from Sweden, Denmark and Finland. N Engl J Med. 2000;343:78-85.
11. Ovsiannikov D, Selinski S, Lehmann ML, Blaszkewicz M, Moormann O, Haenel MW, et al. Polymorphic enzymes, urinary bladder cancer risk, and structural change in the local industry. J Toxicol Environ Health. 2012;75A:557-65.
12. Rafnar T, Vermeulen SH, Sulem P, Thorleifsson G, Aben KK, Witjes JA, et al. European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene. Hum Mol Genet. 2011;20:4268-81.
13. Schwender H, Selinski S, Blaszkewicz M, Marchan R, Ickstadt K, Golka K, et al. Distinct SNP combinations confer susceptibility to urinary bladder cancer in smokers and non-smokers. PLoS One. 2012;7(12):51880.
14. Selinski S, Blaszkewicz M, Lehmann ML, Ovsiannikov D, Moormann O, Guballa C, et al. Genotyping NAT2 with only two SNPs (rs1041983 and rs1801280) outperforms the tagging SNP rs1495741 and is equalivalent to the conventional 7-SNP NAT2 genotype. Pharmacongenet Genomics. 2011;21:673-8.
15. Selinski S, Lehmann ML, Blaszkewicz M, Ovsiannikov D, Moormann O, Guballa C, et al. Rs11892031[A] on chromosome 2q37 in an intronic region of the UGT1A locus is associated with urinary bladder cancer risk. Arch Toxicol. 2012;86:1369-78.
16. Selinski S, Lehmann ML, Blaszkewicz M, Ovsiannikov D, Moormann O, Guballa C, et al. Urinary bladder cancer risk in relation to a single nucleotide polymorphism (rs2854744) in the insulin-like growth factor-binding protein-3 (IGFBP3) gene. Arch Toxicol. 2012;86:195-203.
17. Stewart JD, Marchan R. Polymorphisms hit the headlines. Arch Toxicol. 2012;86:1799-1801.

[*] Corresponding Author:

Seddik Hammad, Department of Forensic Medicine and Veterinary Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt, eMail: el-kariem@ifado.de