In this study, we have examined whether individual or joint modifying effects among four polymorphic metabolic genes were implicated in the development of lung cancer in a Caucasian population from Asturias, Northern Spain. Our results suggest that the polymorphisms CYP1A1 MspI T6235C, GSTM1 present/null, GSTT1 present/null and GSTP1 Ile105Val are not associated with lung cancer risk or cancer subtype.
The analysis performed in the present study between the polymorphisms studied and tobacco consumption did not reveal any gene-environmental interaction. The results showed higher lung cancer risk with higher tobacco consumption. Finally, no association was observed in the analysis of interaction between the polymorphisms studied and occupation.
Our study has several strengths, including high participation levels of eligible cases from a homogeneous population of similar ancestry and all of our control subjects being under Hardy-Weinberg equilibrium. In addition, all of our cases were pathologically confirmed. We also applied a strong quality control from genotyping (explained in detail in Methods section). Inevitably, the use of hospital-based controls is a potential limitation. The hospitals from which the cases were recruited were reference centers for all patients requiring hospitalization. Our controls were referred to these hospitals due to the presence of acute health conditions that were unrelated to lung cancer risk factors. There is always a chance of recall bias consisting of a systematic error due to differences in memories of cigarette smoking habits or occupational exposures between cases and controls. Structured interviews, like those used in this study, help to minimize this type of risk. Moreover, the prevalence of tobacco smoking and occupational exposure was in agreement with the literature. Our sample size is not large enough to find conclusive results in interaction analysis. Other genes that could participate in xenobiotic metabolism were not considered on the current study, which is another possible limitation. Therefore, our future objective is to validate these results with more individuals and powerful genotyping techniques.
Several studies have shown that the CYP1A1 MspI T6235C polymorphism is associated with an increased lung cancer risk in Asian populations, especially in relation to tobacco smoking
[11, 32]. However, previous research, including a review of 20 studies
 and two pooled analyses
[32, 53], in addition to our results suggest that there is not an established association between this polymorphism and increased lung cancer risk in Caucasian populations.
Although biological studies have shown evidence of variant genotypes in the GST genes, including GSTM1, GSTT1 and GSTP1, resulting in reduced enzymatic activity in the cell, epidemiological studies do not support these findings. Many studies, including several meta-analyses and pooled analyses, support our finding that these three polymorphisms are not associated with lung cancer risk
A large meta-analysis conducted in 2006, including 19,729 cases and 25,931 controls from 117 studies
, found an increased lung cancer risk associated with the GSTM1 present/null polymorphism. However, when only studies with more than 500 case/control pairs were considered, no association was observed. Similarly, pooled analyses with either non-smokers from 23 studies
 on cases from a Caucasian population younger than 60 years old with non-small cell lung cancer
 were not significantly related to lung cancer or disease progression.
In relation to the GSTT1 present/null polymorphism, two meta-analyses and three pooled analyses have been performed to date. Similarly to the GSTM1 present/null polymorphism, the meta-analysis carried out by Ye et al.
, including 9,636 cases and 12,322 controls from 44 studies, revealed an increased lung cancer risk associated with the variant genotype of GSTT1. However, when only studies with more than 500 case/control pairs were considered, no association was observed. In addition, a meta-analysis of 34 studies found no association between this polymorphism and lung cancer risk in a Caucasian population
. The three pooled analyses, one including 34 studies
, the second with non-smokers from 8 studies
, and the last including cases of a Caucasian population younger than 60 years old with non-small cell lung cancer
, showed no statistically significant associations.
Finally, a recent meta-analysis including 8,322 cases and 8,844 controls from 27 studies found no association between the GSTP1 Ile105Val polymorphism and lung cancer risk
 among all study participants or stratified by race/ethnicity. These findings corroborate findings from another meta-analysis of 25 studies with 6,221 cases and 7,602 controls
 and with a pooled analysis including cases of a Caucasian population younger than 60 years old with non-small cell lung cancer
Analyses of gene-gene interactions are especially important in the glutathione metabolic pathway where multiple enzymes with overlapping functions and shared substrates have been associated with susceptibility to carcinogens and toxic agents. In this study, no association was found probably due to the failure to consider an exhaustive chart of carcinogen metabolism related genes. However, other studies have found positive results in the gene-gene interaction analysis
[24, 27, 54], which could support the notion that genome-based lung cancer risk is likely to be influenced by combinations of single risk genes of modest effect as well as synergistic gene-gene interactions.
Although it is well established that occupational exposure is an important risk factor for lung cancer
 and the metabolic genes studied here are implicated in the metabolism of important occupational carcinogens
[6, 12, 13], very few studies on genetic variants in these metabolic genes have been able to take occupation into account because of the difficulty to compile that information. Thus, while several studies have analysed the effect of these polymorphisms on the individual susceptibility to different cancers, particularly bladder cancer, while controlling for occupation
[55–58], only five studies to date have controlled by occupational exposure in lung cancer
[5, 29, 59–61]. Nazar-Stewart et al.
 evaluated the occupational exposure to arsenic, asbestos, and welding or diesel products as potential effect modifiers for the GSTM1 present/null, GSTT1 present/null, and GSTP1 Ile105Val polymorphisms but found no association. Jourenkova-Mironova et al.
, Reszka et al.
, and Risch et al.
 used occupational exposure as a confounding variable and Yin et al.
 used occupation as matching variable. No study has used occupational exposure; therefore, we have added to this discussion by evaluating the possible modification of the relationship between workers in high occupational risk and lung cancer development.