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

Background. CYP and GST gene families detoxify tobacco carcinogens and have been linked to the risk of non-small cell lung carcinoma (NSCLC). Aim. 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. Methods. 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 x OR2). Results. 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. Conclusion. Epistatic interactions revealed that CYPs/GSTs might follow a web of the interactions to modify the risk of NSCLC. (C) 2021 Published by Elsevier Inc. on behalf of Instituto Mexicano del Seguro Social (IMSS).

Automated summary

The study demonstrated that genetic variations in CYP2A6, GSTT1, and GSTM1 were significantly associated with the risk of non-small cell lung carcinoma (NSCLC), with GSTM1 (del.)/CYP2A6 (variant) genotype showing the highest risk. Furthermore, complex interactions between different genotypes may modify the risk of NSCLC.