CYP 和 GSTs 基因变异与吸烟独立和交互作用对非小细胞肺癌风险的影响。

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

机构信息

Department of Pathology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, India; Department of Biochemistry, Babu Banarasi Das University, Lucknow, India.

Department of Pathology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, India.

出版信息

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

DOI:10.1016/j.arcmed.2021.05.002

PMID:34092421

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 OR. In contrast, the two ORs' epistatic interaction for the individual genotypes has been represented as OR = OR/(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 (OR = 0.66 and 0.64). A co-suppressive interaction was observed between GSTT1 (del.)/CYP2A6 (Ser/Pro+Pro/Pro) (OR = 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 (OR = 0.15). CYP1A1(TC+CC)/CYP2A13(CT+TT)mutually interacted synergistically (OR = 1.27).CYP1A1 (TC+CC)/GSTP1 (Val/Val+Ile/Val) genotype demonstrated an additive (OR = 1) effect. GSTP1(Val/Val+Ile/Val) interacts with GSTT1 (del.) genotype exerted a suppressive effect (OR = 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.

摘要

背景

CYP 和 GST 基因家族能够解毒烟草致癌物，与非小细胞肺癌（NSCLC）的风险相关。

目的

研究 CYP 和 GST 遗传变异与吸烟对非小细胞肺癌（NSCLC）及其组织学亚型风险的独立和联合作用。

方法

通过两个基因中特定基因型的效应，我们通过 OR（比值比）OR1 和 OR2 来模拟上位性相互作用，将两种基因型的组合特征表示为 OR。相比之下，个体基因型的两个 OR 的上位性相互作用则表示为 OR=OR/(OR1×OR2)。

结果

CYP2A6（OR：4.2，p<0.001）、GSTT1（OR：3.9，p<0.001）和 GSTM1（OR：4.5，p<0.001）的变异基因型与 NSCLC 显著相关。GSTM1（del.）/CYP2A6（变异）基因型与 NSCLC 风险增加相关（OR：12.5，p<0.001）。GSTM1（del.）/CYP2A6（Ser/Pro+Pro/Pro）和 GSTM1（del.）/CYP2A13（CT+TT）表现出冗余的协同作用（OR=0.66 和 0.64）。CYP2A6（Ser/Pro+Pro/Pro）和 GSTT1（del.）之间观察到协同抑制相互作用（OR=0.41）。同时，GSTT1/GSTM1 del. 基因型与 NSCLC 显著相关。相反，GSTT1 del./GSTM1 del. 基因型相互作用表现出协同抑制作用（OR=0.15）。CYP1A1（TC+CC）/CYP2A13（CT+TT）相互作用协同增强（OR=1.27）。CYP1A1（TC+CC）/GSTP1（Val/Val+Ile/Val）基因型表现出加性（OR=1）效应。GSTP1（Val/Val+Ile/Val）与 GSTT1（del.）基因型相互作用表现出抑制作用（OR=0.69）。在吸烟者中，CYP2A6 增加风险 4.2（p=0.001）至 5.6 倍（p<0.001），而 GSTM1 和 GSTT1 与吸烟无关。