lung cancer is one of the leading causes of cancer - related deaths in the world .
although it is well known that smoking is the primary risk factor for lung cancer , lung cancer develops in less than 20% of people who smoke throughout their life . moreover , lung cancer is a multi - cellular and multistage process involving a number of genetic changes in oncogenes , suggesting that genetic factors may play an important role in its development .
the glutathione s - transferases ( gsts ) are a gene superfamily of phase ii metabolic enzymes that detoxify free radicals , particularly in tobacco smoke , products of oxidative stress , and carcinogens such as benzopyrene and other polycyclic aromatic hydrocarbons .
phenotype assays have confirmed this lack of function by demonstrating a strong concordance between phenotype and genotype .
previous studies have suggested that individuals with null genotypes of gstm1 may be unable to eliminate electrophilic carcinogens efficiently and have a high risk of lung cancer .
however , the results from previous reported studies in asians were inconclusive [ 333 ] .
therefore , we conducted a meta - analysis to explore the effect of gstm1 null genotype on lung cancer risk in asians .
we searched the pubmed and embase to identify published case - control studies investigating the associations of gstm1 null genotype with risk of lung cancer in asians .
glutathione s - transferases or  gstm1 and  lung cancer , without restriction on language .
additional studies were identified by a manual search of references of original studies or review articles .
the inclusion criteria were : ( 1 ) original papers containing independent data ; ( 2 ) studies should provide the sample size , odds ratios ( ors ) , and 95% confidence intervals ( cis ) , as well as the genetic distribution or the information needed to infer the results ; and ( 3 ) case - control or cohort studies .
the major exclusion criteria for studies were : ( 1 ) overlapping data ; ( 2 ) insufficiently useful data ; and ( 3 ) case - only studies or family - based studies ; ( 4 ) reviews , abstracts , or commentaries ; ( 5 ) not relevant to lung cancer or gstm1 ; and ( 6 ) not conducted in asians .
two independent researchers extracted raw data according to the inclusion criteria . the following information was collected from each study using a data extraction form : the surname of the first author , year of publication , country of origin , sex of subjects , histology , smoking status , number of cases and controls , adjustment , and ors and the corresponding 95% confidence intervals ( cis ) of lung cancer risk . for the gstm1 gene , we estimated the risk effect of the null genotype on lung cancer compared with the non - null genotypes in the recessive model ( null vs. heterozygous + wild type ) .
the strength of the association between the gstm1 gene and lung cancer risk was measured by ors with 95% cis .
the ors with corresponding 95% cis from individual studies were pooled using fixed or random effects models , according to the heterogeneity .
when the p value for cochran s q statistic was less than 0.1 , and a significant heterogeneity existed across the included studies , the random effects model ( dersimonian and laird method ) was used for meta - analysis , or the fixed - effects model ( mantel - haenszel method ) was used .
sensitivity analysis was further performed by excluding a single study to assess the impact of an individual study on the pooled estimate .
funnel plots and egger s regression test were used to assess the potential publication bias .
data analysis was performed using stata 12 ( statacorp lp , college station , texas , usa ) .
we searched the pubmed and embase to identify published case - control studies investigating the associations of gstm1 null genotype with risk of lung cancer in asians .
glutathione s - transferases or  gstm1 and  lung cancer , without restriction on language .
additional studies were identified by a manual search of references of original studies or review articles .
the inclusion criteria were : ( 1 ) original papers containing independent data ; ( 2 ) studies should provide the sample size , odds ratios ( ors ) , and 95% confidence intervals ( cis ) , as well as the genetic distribution or the information needed to infer the results ; and ( 3 ) case - control or cohort studies .
the major exclusion criteria for studies were : ( 1 ) overlapping data ; ( 2 ) insufficiently useful data ; and ( 3 ) case - only studies or family - based studies ; ( 4 ) reviews , abstracts , or commentaries ; ( 5 ) not relevant to lung cancer or gstm1 ; and ( 6 ) not conducted in asians .
the following information was collected from each study using a data extraction form : the surname of the first author , year of publication , country of origin , sex of subjects , histology , smoking status , number of cases and controls , adjustment , and ors and the corresponding 95% confidence intervals ( cis ) of lung cancer risk .
for the gstm1 gene , we estimated the risk effect of the null genotype on lung cancer compared with the non - null genotypes in the recessive model ( null vs. heterozygous + wild type ) .
the strength of the association between the gstm1 gene and lung cancer risk was measured by ors with 95% cis .
the ors with corresponding 95% cis from individual studies were pooled using fixed or random effects models , according to the heterogeneity .
when the p value for cochran s q statistic was less than 0.1 , and a significant heterogeneity existed across the included studies , the random effects model ( dersimonian and laird method ) was used for meta - analysis , or the fixed - effects model ( mantel - haenszel method ) was used .
sensitivity analysis was further performed by excluding a single study to assess the impact of an individual study on the pooled estimate .
funnel plots and egger s regression test were used to assess the potential publication bias .
data analysis was performed using stata 12 ( statacorp lp , college station , texas , usa ) .
a total of 31 studies were retrieved based on the search criteria for lung cancer susceptibility related to the gstm1 polymorphism [ 333 ] .
the evaluations of the association between gstm1 polymorphism and lung cancer risk are summarized in table 2 .
the null genotype of gstm1 was associated with a significantly increased risk of lung cancer when compared with present genotype ( or=1.43 ; 95% ci , 1.301.58 ; figure 2 ) .
the combination of adjusted ors for lung cancer was 1.38 ( 95% ci , 1.231.54 ) . when stratified by sex , significantly elevated risks were observed in men ( or=1.38 ; 95% ci , 1.061.78 ) and women ( or=1.30 ; 95% ci , 1.031.64 ) . in the subgroup analysis according to histology , significantly increased risks were observed in adenocarcinoma ( or=1.27 ; 95% ci , 1.051.55 ) and squamous cell carcinoma ( or=1.40 ; 95% ci , 1.101.78 ) , but not in small - cell lung cancer ( or=1.22 ; 95% ci , 0.811.83 ) .
subgroup analysis based on the smoking status showed that increased risks were found in non - smokers ( or=1.49 ; 95% ci , 1.251.79 ) and smokers ( or=1.78 ; 95% ci , 1.432.23 ) . as shown in figure 3 ,
the results showed that the pooled ors tended to be stable . a single study involved in the meta - analysis
was deleted each time to reflect the influence of the individual data set on the pooled ors , and the corresponding pooled ors were not materially altered ( figure 4 ) .
funnel plot and egger s test were used to assess the publication bias of the literature .
the shape of the funnel plot did not reveal any evidence of obvious asymmetry ( figure 5 ) .
a total of 31 studies were retrieved based on the search criteria for lung cancer susceptibility related to the gstm1 polymorphism [ 333 ] .
the evaluations of the association between gstm1 polymorphism and lung cancer risk are summarized in table 2 .
the null genotype of gstm1 was associated with a significantly increased risk of lung cancer when compared with present genotype ( or=1.43 ; 95% ci , 1.301.58 ; figure 2 ) .
the combination of adjusted ors for lung cancer was 1.38 ( 95% ci , 1.231.54 ) . when stratified by sex , significantly elevated risks were observed in men ( or=1.38 ; 95% ci , 1.061.78 ) and women ( or=1.30 ; 95% ci , 1.031.64 ) . in the subgroup analysis according to histology , significantly increased risks were observed in adenocarcinoma ( or=1.27 ; 95% ci , 1.051.55 ) and squamous cell carcinoma ( or=1.40 ; 95% ci , 1.101.78 ) , but not in small - cell lung cancer ( or=1.22 ; 95% ci , 0.811.83 ) .
subgroup analysis based on the smoking status showed that increased risks were found in non - smokers ( or=1.49 ; 95% ci , 1.251.79 ) and smokers ( or=1.78 ; 95% ci , 1.432.23 ) . as shown in figure 3 ,
the results showed that the pooled ors tended to be stable . a single study involved in the meta - analysis
was deleted each time to reflect the influence of the individual data set on the pooled ors , and the corresponding pooled ors were not materially altered ( figure 4 ) .
funnel plot and egger s test were used to assess the publication bias of the literature .
the shape of the funnel plot did not reveal any evidence of obvious asymmetry ( figure 5 ) .
the present meta - analysis , including 5347 lung cancer cases and 6072 controls from 31 case - control studies , explored the association of gstm1 null genotype with lung cancer risk .
we demonstrated that the null genotype of gstm1 was associated with a significantly increased lung cancer risk in asians .
furthermore , in the stratified analysis by sex , we found that both men and women with gstm1 null genotype had increased lung cancer risk .
more studies are needed to assess the association between gstm1 null genotype and lung cancer risk in males and females .
cigarette smoking is a pro - inflammatory stimulus and an important risk factor for lung cancer .
our results showed significant associations between gstm1 polymorphism and lung cancer risk among smokers and non - smokers .
we also found that patients with gstm1 null genotype had increased non  small - cell lung cancer ( adenocarcinoma and squamous cell carcinoma ) risk .
however , we failed to find a significant relationship between gstm1 null polymorphism and small - cell lung cancer risk .
this result suggested that gstm1 null polymorphism may play an important role in the development of non - small - cell lung cancer .
gsts are biotransformation enzymes , and they are phase ii enzymes with both catalytic activities and non - catalytic functions .
previous studies have shown that individuals with the gstm1 null genotype have a decreased capacity to detoxify certain carcinogens .
thus , it is biologically plausible that the gstm1 null genotype may increase risk of lung cancer .
first , the methodological issues for meta - analysis such as one - way sensitivity analysis and cumulative meta - analysis were well investigated .
results from one - way sensitivity analysis and cumulative meta - analysis suggested high stability and reliability of our results and significant heterogeneity was not observed in this meta - analysis . moreover , funnel plots and egger s tests were used to find potential publication bias .
second , lack of the original data from the eligible studies limited the evaluation of the effects of the gene - gene and gene - environment interactions in the development of lung cancer .
third , only published studies were included in this meta - analysis ; therefore , publication bias may have occurred even though the statistical test did not show it .
in conclusion , this meta - analysis suggests that an increased risk of lung cancer was associated with the null polymorphism of gstm1 in asians .
 backgroundseveral molecular epidemiological studies have been conducted to examine the association between glutathione s - transferase m 1 ( gstm1 ) null genotype and lung cancer in asians ; however , the conclusions remained controversial . 
 we therefore performed an extensive meta - analysis on 31 published case - control studies with a total of 5347 lung cancer cases and 6072 controls.material/methodspubmed and embase were searched to identify case - control studies investigating the associations of gstm1 null genotype with risk of lung cancer in asians . 
 odds ratios ( ors ) with 95% confidence intervals ( cis ) were used to assess the strength of association between lung cancer risk and polymorphism of gstm1.resultsgstm1 null genotype was significantly associated with lung cancer risk ( or=1.43 ; 95% ci , 1.301.58 ) . 
 this result remained statistically significant when the adjusted ors were combined ( or=1.38 ; 95% ci , 1.231.54 ) . in the subgroup analysis by sex 
 , there were significant associations in women and men . 
 when stratifying for histology , this genotype showed increased adenocarcinoma risk and squamous cell carcinoma risk . in the subgroup analysis stratified by smoking status , lung cancer risk was increased in both smokers and non-smokers.conclusionsthis study suggests that gstm1 null genotype is a risk factor for lung cancer in asians . 