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DNA Repair Polymorphisms Modify Bladder Cancer Risk: A Multi-factor Analytic StrategyAndrew A.S.a · Karagas M.R.a · Nelson H.H.e · Guarrera S.c · Polidoro S.c · Gamberini S.c · Sacerdote C.c · Moore J.H.b · Kelsey K.T.f · Demidenko E.a · Vineis P.c, g · Matullo G.c, d
aDepartment of Community and Family Medicine, Section of Biostatistics and Epidemiology, and bDepartment of Genetics, Computational Genetics Laboratory, Dartmouth Medical School, Lebanon, N.H., USA; cI.S.I Foundation and dDepartment of Genetics, Biology and Biochemistry, Torino, Italy; Departments of eEnvironmental Health and fGenetics and Complex Diseases, Harvard School of Public Health, Boston, Mass., gImperial College London, St Mary’s Campus, London, UK Corresponding Author
Dr. Angeline S. Andrew
Dartmouth Medical School
Section of Biostatistics and Epidemiology , 7927 Rubin 860
One Medical Center Drive, Lebanon, NH 03756
Tel. +1 603 653 9019, Fax +1 603 653 9093, E-Mail Angeline.Andrew@dartmouth.edu
Objectives: A number of common non-synonymous single nucleotide polymorphisms (SNPs) in DNA repair genes have been reported to modify bladder cancer risk. These include: APE1-Asn148Gln, XRCC1-Arg399Gln and XRCC1-Arg194Trp in the BER pathway, XPD-Gln751Lys in the NER pathway and XRCC3-Thr241Met in the DSB repair pathway. Methods: To examine the independent and interacting effects of these SNPs in a large study group, we analyzed these genotypes in 1,029 cases and 1,281 controls enrolled in two case-control studies of incident bladder cancer, one conducted in New Hampshire, USA and the other in Turin, Italy. Results: The odds ratio among current smokers with the variant XRCC3-241 (TT) genotype was 1.7 (95% CI 1.0–2.7) compared to wild-type. We evaluated gene-environment and gene-gene interactions using four analytic approaches: logistic regression, Multifactor Dimensionality Reduction (MDR), hierarchical interaction graphs, classification and regression trees (CART), and logic regression analyses. All five methods supported a gene-gene interaction between XRCC1-399/XRCC3-241 (p = 0.001) (adjusted OR for XRCC1-399 GG, XRCC3-241 TT vs. wild-type 2.0 (95% CI 1.4–3.0)). Three methods predicted an interaction between XRCC1-399/XPD-751 (p = 0.008) (adjusted OR for XRCC1-399 GA or AA, XRCC3-241 AA vs. wild-type 1.4 (95% CI 1.1–2.0)). Conclusions: These results support the hypothesis that common polymorphisms in DNA repair genes modify bladder cancer risk and highlight the value of using multiple complementary analytic approaches to identify multi-factor interactions.
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