A systematic approach to analysing gene-gene interactions:: Polymorphisms at the microsomal epoxide hydrolase EPHX and glutathione S-transferase GSTM1, GSTT1, and GSTP1 loci and breast cancer risk

Objective: We undertook a case-control study in an Australian Caucasian population-based sample of 1,246 cases and 664 controls to assess the roles 3 of detoxification gene polymorphisms EPHX T > C Tyr(113)His, GSTT1 deletion, GSTM1 deletion, and GSTP1 A > G Ile(105)Val on risk of breast cancer. Methods: We systematically addressed the main effects and possible gene-gene interactions using unconditional logistic regression to estimate odds ratios (OR) adjusted for potential confounders and using standard model building approaches based on likelihood theory. Results: There was a decreased risk associated with the EPHX CC genotype [OR, 0.60; 95%, confidence interval (95% CI), 0.43-0.84; P = 0.0031, marginally significant evidence of increased risk with GSTM1 null genotype (OR, 1.21; 95% Cl, 1.00-1.47; P = 0.05), but no association with GSTT1 null genotype (OR, 1.12; 95% Cl, 0.86-1.45; P = 0.4) or GSTP1 (OR, 0.95; 95% Cl, 0.82-1.10; P = 0.5) genotype. The full model with all interactions gave a significantly better fit than a main-effects-only model (P < 0.001), providing evidence for gene-gene interactions. The most parsimonious model included main effects for EPHX, GSTT1, and GSTM1; a two-way interaction between EPHX and GSTM1; and a three-way interaction between EPHX, GSTM1, and GSTT1. Predicted risks were greatest for women carrying deletions of both GSTT1 and GSTM1, with either the EPHX TC genotype (OR, 2.02; 95% Cl, 1.19-3.45; P = 0.009) or EPHX CC genotype (OR, 3.54; 95% Cl, 1.29-9.72; P = 0.14). Conclusion: Detoxification gene polymorphisms may interact with each other to result in small groups of individuals at modestly increased risk. We caution against over-interpretation and suggest that pooling of similarly large studies is needed to clarify the possible role of such complex gene-gene interactions on breast cancer risk.