BMC Cancer 2009, 9:397 http://www.biomedcentral.com/1471-2407/9/397 Table 3: Multifactor Dimensionality Reduction Models for GST gene variations and prostate cancer risk Best Model Cross Validation Consistency (CVC) Average Testing Accuracy (ATA) Permutation Testing p-value One Factor GSTP1 Two Factor GSTP1 GSTM1 10/10 8/10 cation would have a higher risk of developing PCA. In an exploratory analysis, we investigated the effects of ciga- rette smoking combined with these polymorphisms in relation to PCA risk. This increased risk may be partially attributed to exposure to tobacco carcinogens and altered capacity to metabolically detoxify hazardous compounds. Logistic regression analysis revealed a moderately signifi- cant association between PCA susceptibility and GSTP1 105 Val. These findings were confirmed using a robust data-mining tool specifically designed to evaluate main effects and higher order interactions. Although we did not detect any significant single gene effects among GSTM1 and T1 deletions, we did observe a moderately synergistic interaction between GSTP1-GSTM1 and PCA susceptibil- ity. We found a 2.1-fold increase in PCA risk associated with men possessing 2-3 high risk alleles with the GSTP1 GG (Val/Val) &GSTM1 *1/*1 + *1/*0 genotype according to logistic regression analysis. Numerous previous studies have investigated the role of these GST polymorphisms in relation to PCA susceptibil- ity. For example, Agalliu et al. 2006 reported a moderate increase in PCA risk associated with the GSTM1 gene dele- tion for Caucasian men (OR = 1.54; 95%CI = 1.19-2.01); however, GSTT1 deletion and GSTP1 105 Val polymor- phisms were not significantly associated with prostate 0.530 0.535 0.001 0.01 cancer[5]. The findings for GSTT1 and GSTP1 were corroborated in a recent meta-analysis of pooled data from ≥ 3,837 cases and ≥ 4,552 controls[12]. This same report, however, observed a 1.3 fold increase in PCA risk among all study participants was associated with the GSTM1*0 loci using pooled data from 4,564 cases and 5,464 controls (OR = 1.33; 95%CI = 1.15-1.55)[12]. Strat- ification based on self-identified race indicated that risk estimates were comparable between Caucasians and Asians; however, the GSTM1 and GSTT1 deletion poly- morphisms did not modify risk among Africans or Afri- can-Americans[12]. Interestingly, only two published studies investigated the role of the GSTP1 105 Val SNP in relation to PCA among men of African descent[5,12,54]. The findings in these two reports may be partially attributed to the failure to utilize rigorous statistical tools that permit the evaluation of main effects even in the pres- ence of small sample sizes (i.e., at least 200 cases and 200 controls) such as MDR. The MDR selection of the GSTP1 105 Val loci as a significant PCA predictor in the current study is promising and will undergo subsequent valida- tion within future studies among men of African descent. We have considered the strengths and limitations of the current study. Although MDR doesn't allow for adjust- ments of covariates, it does control for multiple compari- Table 4: Combined effects of GST polymorphisms and smoking on prostate cancer risk Gene Polymorphism Adjusted OR (95% CI) for Non- smokers†‡ Adjusted OR (95% CI) for Ever- smokers††‡ p-value for Interaction GSTP1 A313G Ile105Val GSTM1 *1/*1 + *1/*0 Deletion *0/*0 GSTT1 *1/*1 + *1/*0 Deletion *0/*0 AA (Ile/Ile) & AG (Ile/Val) 1.00 (Reference) GG (Val/Val) 1.91 (0.47-7.82) 1.00 (Reference) 1.61 (0.36-7.28) 1.00 (Reference) 1.02 (0.21-4.94) 2.88 (0.49-16.82) 1.42 (0.33-6.10) 1.71 (0.59-4.97) 0.47 (0.11-2.09) 1.03 (0.37-2.89) 2.12 (0.47-9.57) 0.928 0.135 0.410 †Associations were determined using multivariate logistic regression models to estimate the risk of developing PCA using GSTP1 105 Ile/Ile, GSTM1 *1/*1 + *1/*0 and GSTT1 *1/*1 + *1/*0 as the Reference genotypes. ††Risk estimates adjusted for age (continuous variable); prostate specific antigen (continuous variable); and West African Ancestry, WAA or admixture (continuous variable). ‡Non-smokers are subjects that have never smoked; Ever-smokers are subjects that are current or former smokers Page 7 of 10 (page number not for citation purposes)