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. 2021 Oct;52(7):719-730.
doi: 10.1016/j.arcmed.2021.05.002. Epub 2021 Jun 4.

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

Anumesh K Pathak  1 , Nuzhat Husain  2 , Surya Kant  3 , Lakshmi Bala  4
Affiliations

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

Anumesh K Pathak et al. Arch Med Res. 2021 Oct.

Abstract

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 × 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.

Keywords: CYP; Epistatic Interaction; GST; Genetic variation; NSCLC; Tobacco smoke.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing personal or financial interest's relationships that could have appeared to influence the research work reported in this manuscript.

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