Multiple Analytical Approaches Reveal Distinct Gene-Environment Interactions in Smokers and Non Smokers in Lung Cancer

Abstract

Complex disease such as cancer results from interactions of multiple genetic and environmental factors. Studying these factors singularly cannot explain the underlying pathogenetic mechanism of the disease. Multi-analytical approach, including logistic regression (LR), classification and regression tree (CART) and multifactor dimensionality reduction (MDR), was applied in 188 lung cancer cases and 290 controls to explore high order interactions among xenobiotic metabolizing genes and environmental risk factors. Smoking was identified as the predominant risk factor by all three analytical approaches. Individually, CYP1A1*2A polymorphism was significantly associated with increased lung cancer risk (OR = 1.69;95%CI = 1.11–2.59,p = 0.01), whereas EPHX1 Tyr113His and SULT1A1 Arg213His conferred reduced risk (OR = 0.40;95%CI = 0.25–0.65,p<0.001 and OR = 0.51;95%CI = 0.33–0.78,p = 0.002 respectively). In smokers, EPHX1 Tyr113His and SULT1A1 Arg213His polymorphisms reduced the risk of lung cancer, whereas CYP1A1*2A, CYP1A1*2C and GSTP1 Ile105Val imparted increased risk in non-smokers only. While exploring non-linear interactions through CART analysis, smokers carrying the combination of EPHX1 113TC (Tyr/His), SULT1A1 213GG (Arg/Arg) or AA (His/His) and GSTM1 null genotypes showed the highest risk for lung cancer (OR = 3.73;95%CI = 1.33–10.55,p = 0.006), whereas combined effect of CYP1A1*2A 6235CC or TC, SULT1A1 213GG (Arg/Arg) and betel quid chewing showed maximum risk in non-smokers (OR = 2.93;95%CI = 1.15–7.51,p = 0.01). MDR analysis identified two distinct predictor models for the risk of lung cancer in smokers (tobacco chewing, EPHX1 Tyr113His, and SULT1A1 Arg213His) and non-smokers (CYP1A1*2A, GSTP1 Ile105Val and SULT1A1 Arg213His) with testing balance accuracy (TBA) of 0.6436 and 0.6677 respectively. Interaction entropy interpretations of MDR results showed non-additive interactions of tobacco chewing with SULT1A1 Arg213His and EPHX1 Tyr113His in smokers and SULT1A1 Arg213His with GSTP1 Ile105Val and CYP1A1*2C in nonsmokers. These results identified distinct gene-gene and gene environment interactions in smokers and non-smokers, which confirms the importance of multifactorial interaction in risk assessment of lung cancer.

Susceptibility of Lung Cancer with Polymorphisms of CYP1A1, GSTM1, GSTM3, GSTT1 and GSTP1 Genotypes in the Population of Inner Mongolia Region

“…Both GSTM1 and GSTT1 gene exhibit an inherited homozygous deletion polymorphism (null genotype), which has been associated with the loss of enzymatic activity and increased vulnerability to cytogenetic damage (Norppa, 2004). As a result of decreased efficiency in protection against carcinogens, the individuals with homozygous deletion polymorphism are considered to be at an increased risk for malignancies (Hayes et al, 2005;Mcllwain et al, 2006;Singh et al, 2010;Ihsan et al, 2011). Many studies have been published on the association of CYP1A1 and GSTM1 polymorphisms and lung cancer susceptibility with inconsistent findings.…”

“…Many studies have been published on the association of CYP1A1 and GSTM1 polymorphisms and lung cancer susceptibility with inconsistent findings. Some of the studies showed the relationship between the polymorphisms of GSTM1 and CYP1A1 Ile/Val genotype (Singh et al, 2010;Ihsan et al, 2011) but other results are contradictory (Le Marchand et al, 1998;London et al, 2000). However, some data of Chinese Han population (Shi et al, 2008) and little data on Mongolian population are still available.…”

Polymorphisms in DNA repair genes of XRCC1, XPA, XPC, XPD and associations with lung cancer risk in Chinese people

“…Secondly, lung cancer is a complex multifactorial disease, which occurs by multiple gene-gene and multiple geneenvironment interplay, thus, the effect of single SNP and a single gene does not adequately represent lung cancer risk. 46,47 Therefore, our study examined multiple SNPs in different DNA repair pathways. The HapMap database can provide wide coverage of common variations.…”

Quantitative assessment of the effects of the EPHX1 Tyr113His polymorphism on lung and breast cancer

“…A total of 14 studies (Benhamou et al, 1998;Persson et al, 1999;London et al, 2000;To-Figueras et al, 2001;Wu et al, 2001;Yin et al, 2001;Cajas-Salazar et al, 2003;Gsur et al, 2003;Harms et al, 2004;Liang et al, 2004;Voho et al, 2006;Timofeeva et al, 2010;Ihsan et al, 2011;Tilak et al, 2011) that included full-text articles and complied with HWE demonstrated an association between the EPHX1 Tyr113His polymorphism and lung cancer (Table 1). Among the studies included, 2 included 2 ethnicity types (London et al, 2000;Wu et al, 2001), and the data was collected separately and served as independent studies in our meta-analyses.…”