Independent and Interactive Effect of CYPs and GSTs Genetic Variants and Tobacco Smoking on the Risk of Non-Small Cell Lung Carcinoma

Abstract

CYP and GST gene families detoxify tobacco carcinogens and have been linked to the risk of non-small cell lung carcinoma (NSCLC). Independent and combined effects of CYP and GST genetic variations and smoking on the risk of non-small cell lung carcinoma (NSCLC) and its sub-histological types. We modelled an epistatic interaction via the effects of particular genotypes in two genes as OR (odds ratio), OR1, and OR2, a combination of both genotypes were characterized as ORcombine. In contrast, the two ORs' epistatic interaction for the individual genotypes has been represented as ORinteraction = ORcombine/(OR1 × OR2). The variant genotypes of CYP2A6 (OR:4.2, p <0.001), GSTT1 (OR:3.9, p <0.001), and GSTM1 (OR: 4.5, p <0.001) were showed a significant risk with NSCLC. GSTM1 (del.)/CYP2A6 (variant) genotype was associated with a higher risk of NSCLC (OR:12.5, p <0.001). GSTM1 (del.)/CYP2A6 (Ser/Pro+Pro/Pro) and GSTM1 (del.)/CYP2A13 (CT+TT) interacted redundantly (ORintraction = 0.66 and 0.64). A co-suppressive interaction was observed between GSTT1 (del.)/CYP2A6 (Ser/Pro+Pro/Pro) (ORintraction = 0.41). Simultaneously, both GSTT1/GSTM1 del. genotype was associated with a significantly higher risk to NSCLC. In contrast, GSTT1 del./GSTM1 del. genotype interaction displayed a co-suppressive effect (ORintraction = 0.15). CYP1A1(TC+CC)/CYP2A13(CT+TT)mutually interacted synergistically (ORintraction = 1.27).CYP1A1 (TC+CC)/GSTP1 (Val/Val+Ile/Val) genotype demonstrated an additive (ORintraction = 1) effect. GSTP1(Val/Val+Ile/Val) interacts with GSTT1 (del.) genotype exerted a suppressive effect (ORintraction = 0.69). CYP2A6 in smokers increased risk by 4.2 (p = 0.001) to 5.6 fold (p <0.001), while GSTM1 and GSTT1 were independent of smoking. Epistatic interactions revealed that CYPs/GSTs might follow a web of the interactions to modify the risk of NSCLC.