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

Spurdle AB, Chang JH, Byrnes GB, Chen X, Dite GS, McCredie MR, Giles GG, Southey MC, Chenevix-Trench G, Hopper JL (2007) 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. Cancer Epidemiol Biomarkers Prev 16:769-774

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 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 = 0.003], marginally significant evidence of increased risk with GSTM1 null genotype (OR, 1.21; 95% CI, 1.00-1.47; P = 0.05), but no association with GSTT1 null genotype (OR, 1.12; 95% CI, 0.86-1.45; P = 0.4) or GSTP1 (OR, 0.95; 95% CI, 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%="" ci,="" 1.19-3.45;="" p="0.009)" or="" ephx="" cc="" genotype="" (or,="" 3.54;="" 95%="" ci,="" 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="" overinterpretation="" 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.="">