DNA repair polymorphisms modify bladder cancer risk: a multi-factor analytic strategy.
OBJECTIVE
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.
Andrew
Angeline S
AS
Department of Community and Family Medicine, Section of Biostatistics and Epidemiology, Dartmouth Medical School, Lebanon, NH 03756, USA. Angeline.Andrew@dartmouth.edu
Karagas
Margaret R
MR
Nelson
Heather H
HH
Guarrera
Simonetta
S
Polidoro
Silvia
S
Gamberini
Sara
S
Sacerdote
Carlotta
C
Moore
Jason H
JH
Kelsey
Karl T
KT
Demidenko
Eugene
E
Vineis
Paolo
P
Matullo
Giuseppe
G
D000328:Adult; D000368:Aged; D004260:DNA Repair / Q000235:genetics*; D005163:Factor Analysis, Statistical; D006801:Humans; D007258:Informed Consent; D007407:Interviews as Topic; D007558:Italy; D008875:Middle Aged; D008957:Models, Genetic; D009513:New Hampshire / Q000453:epidemiology; D011110:Polymorphism, Genetic; D012042:Registries; D012044:Regression Analysis; D012307:Risk Factors; D001749:Urinary Bladder Neoplasms / Q000453:epidemiology / Q000235:genetics*