| BackgroundColorectal cancer is the third malignant tumors of the world, In terms of incidence, colorectal cancer ranks fourth in men and third in women. There were about 1.361 millian new cases of colorectal cancer worldwide in 2012, and it caused more about 694,000 annual deaths worldwide, the incidence was 9.7%,the mortality was 8.5%。It is most frequent in North America,Western Europe, New-Zealand, Australia and the southern part of South America。Some of the more developed and westernized Asian countries have already experienced a rapidly rising trend at present, and the incidence is similar to the west。Colorectal cancer development requires a complex interaction between genetic and specific environmental,life style risk factors with different degrees of involvement。The increasing incidence rates may be due to some environmental factors, which can lead to the carcinogenesis of colorectal cancer. Some epidemiological studies have revealed that smoking,diets high in red meat, low in vegetables and fiber and obesity are probably important etiological factors increasing the risk of developing colorectal cancer[5-7]。Fearon ER and his colleague found that some mutants/variants contribute to the pathogenesis of the sporadic and inherited forms colorectal cancer, including Glutathione S-transferases (GSTs) genotype. Genetic susceptibility to the tumor with a feware dominant genetic defects, most associated with genetic metabolic enzyme polymorphism.GSTs are a super-family of phase Ⅱ detoxification enzymes which play critical roles in the detoxification of exogenous and endogenous reactive species through conversion of toxic compounds to hydrophilic metabolites.To date, there are 8 classes of GSTs including alpha (a), kappa (κ), mu (μ), omega (ω), pi(π), sigma(σ), theta (θ) and zeta(ζ) have been verified,and polymorphisms have been identified in several of these genes. Glutathione S-transferase M1(GSTMI) which encodes the mu class of GSTs plays vital roles in protecting hosts against cancers.The mu GST enzymes are more effective at the process of detoxifying cytotoxic and genotoxic reactive species than other GSTs.GSTM1 gene has three genotypes: GSTMI (+/+), GSTMI (+/-) and GSTMI (-/-);the GSTM1(-/-) called GSTMI null, Among those three polymorphisms, a null variant (GSTMI*0 allele) is the most common polymorphism of the GSTMI gene, in 2000, Cotton etal reviewed GSTM1 null genotype frequencies in different races,and the frequencies for null was approximately 39%-62% in Caucasions,and 33 to 63 in Asians.the GSTMI null variant result in the loss of enzyme activity, and individuals carried the variant are proven to be associated with genetic risk to cancers.GSTMI has been identified to be implicated in the pathogenesis and development of certain cancers (including colorectal cancer).There are many genetic studies observed that the GSTM1 null variant was related to the risk of cancers.In addition, the GSTM1 null variant has been demonstrated to be linked to an early onset in colorectal cancer. However, the previous studies which aimed to investigate the association of GSTM1 polymorphism and colorectal cancer risk in Chinese populations are inconsistent, and the results of Asians are also controversial. To verify the relationship between GSTM1 null variant and genetic susceptibility to colorectal cancer more comprehensively, we conducted a meta-analysis of case-control studies and cohort studies in Asian.Methods1.Search StrategySystematic electronic searched of PubMed, Chinese Biomedical Database, Chinese National Knowledge from 1996-01-01 to 2014-12-31 were performed to identify the published epidemiological studies on GSTM1 polymorphism and risk of colorectal cancer without any language restriction.The electronic investigation was supplemented by the screening of the references of retrieved articles.2.Seletion CriteriaStrict inclusion and exclusion criteria were determined before data analyses.and data were reviewed and extracted by 2 independent investigators.Quality of the included studies was evaluated independently using Newcastle-Ottawa Scale (NOS), NOS Score is greater than or equal to 5 points can be included in the study. The data from the eligible studies was also independently extracted by two investigators. The following information was respectively extracted:first author’s name, publication year, country where the study was carried out, ethnicity of subjects, numbers of cases and controls, and the genotype distributions of GSTM1 polymorphism.3.Heterogeneity testFor each genetic contrast,heterogeneity was assessed usingchi-square-based Q test, considered significant for P<0.10.The degree of heterogeneity was assessed using I2 statistic[23].with higher values denoting greater degree of heterogeneity (I2=0% to 25%:no heterogeneity; I2=25% to 50%:moderate heterogeneity; I2=50% to 75%:large heterogeneity;I2=75% to 100%:extreme heterogeneity).Assessed hetergeneity Combined with P Value and I2,if I2≥50%, or P≤0.1 and I2≥25% can be concluded that there is statistical heterogeneity;If I2≤25%,或P>0.1 and I2<50% Can be concluded that heterogeneity is small, heterogeniety can be ignored.4.The choice of effect modelThe pooled estimate was combined by a random effect model(DerSimonian-Laird method) or a fixed effect model (Mantel-Haenszel method) according to whether the heterogeneity existed or not.If no significant heterogeneity was detected, the fixed-effect model was chosen,otherwise, the random-effect model was chosen.5.Subgroup and Sensitivity analysisSubgroup analysis based on ethnicity and study design were further conducted respectively to explore the potential sources of heterogeneity.The country subgroups were categorized into three groups (Chinese group,Japanese group,the rest five other countries group).The study type subgroups were categorized into two groups (case control study group,cohort study group).In addition,sensitivity analysis were also employed. In sensitivity analysis,each study was excluded one at a time to determine the the magnitude of influence on the overall summary estimate.Sensitivity analysis was performed to elucidate the stability of the outcomes.6.Publication biasPublication bias was qualitatively evaluated by funnel plot.If the funnel plot is asymmetric,publication bias can be concluded,the more the asymmetric,the greater the degree of publication bias;otherwise,there is no publication bias.7.Statistical analysisAll statistical analyses were assessed with the RevMan 5.0 program (Cochrane Collaboration) (http://www.cochrane.org/revman) based on data from reported Asian populations.the strength of association between GSTM1 null and colorectal cancer was assessed by crude ORs with corresponding 95%CIs,and Z test to calculate the the significance of OR value.P value threshold set for 0.05,All the P values were two sided.It is considered significant for P<0.05, P<0.5 can be concluded that there is statistical differences.We used the forest plot to analysis combined result intuitively.Results1.Literature research resultsFlowing PRISMA procedures,391 potential studies were screened after literature search using the mentioned search strategy.We excluded 321 repeat or not related study after screened title and abstract. However,after reading the full articles,we excluded 4 studies that the genotype data of cases or control could not be abstracted,11 Non-asian studies,12 repeated studies,5 can’t find full articles,4 reviews or Meta analysises,4 studies did not describe the association between the GSTM1 and the risk of colorectal cancer,1 meeting abstract.After Quality evaluation by Newcastle-Ottawa Scale (NOS),29 studies scored 5 points or above 5 points. Finally, only 29 studies met the predetermined inclusion criteria,and they were included in this meta-analysis.Fig.1 shows the process of study selection and exclusion,with specification of reasons.2.Characteristics of eligible studiesIn total, there are 19524 individuals comprising of 7440 (GSTM 1 null 3969) cases of colorectal cancer and 12O84(GSTM1 null 6121) healthy controls from those given studies were included in the meta-analysis.The 29 studies were categorized by language,16 studies were in English, and the other 13 studies were published in Chinese;categorized by country,20 studies from Chinese mainland,4 studies from Japan,1 studies from Indian; 1 studies from singapore; 1 studies from Taiwan;1 studies from Iran; 1 studies from korea; categorized by study type,5 cohort studies,24 case control studies.The characteristics of those eligible studies in Asians were shown in Table 1.3. Overall analysisThere was a moderate heterogeneity among these validation studies in Asian cohorts (P= 0.04,12= 34%).the Random-effect model was chosen to analysis data. Overall, the pooled meta-analysis of eligible studies suggests that GSTM1 null genotype was associated with colorectal cancer risk in Asian populations (Z= 3.10, P= 0.002, OR合并= 1.14,95% CI:1.05-1.25) in a random-effect model (Figure.2).4. Subgroup resultStudy type subgroupsCase control study subgroup included 24 studies,there are 12960 individuals comprising of 5987 (GSTM1 null 2761) cases of colorectal cancer and 6973(GSTM1 null 3616) healthy controls. A test for heterogeneity between studies showed moderate heterogeneity (P= 0.01, I2= 43%). Therefore, the random-effect model was applied and the result indicated that GSTM1 null genotype was associated with colorectal cancer risk in case control subgroup(P-0.003, OR合 并=1.18,95% CI:1.06-1.32;Figure 3;Table 2)Cohort study subgroup included 5 studies,there are 6564 individuals comprising of 1453 (GSTM1 null 743) cases of colorectal cancer and 5111(GSTM1 null 2505) healthy controls. A test for heterogeneity between studies showed no heterogeneity (P= 0.65, I2= 0). Therefore, the fixed-effect model was applied and the result did not indicate any significant association between GSTM1 null genotype and the risk of colorectal cancer (P=0.16, OR合并=1.09,95% CI:1.06-1.32;Fig.4;Table 2).Because 5 studies included in Cohort study come from Chinese population, we made Chinese case control study subgroup。This subgroup included 15 studies,there are 4639 individuals comprising of 1828 (GSTM1 null 1063) cases of colorectal cancer and 2811(GSTM1 null 1484) healthy controls. A test for heterogeneity between studies showed a little evidence of heterogeneity and can be ignored (P= 0. 11,12=33%). Therefore, the fixed-effect model was applied and the result indicated that GSTM1 null genotype was associated with colorectal cancer risk in Chinese case control study (P=0.0003, OR合并=1.25,95% CI:1.11-1.42;Figure 5;Table 2).Country subgroupsChinese subgroup included 20 studies,there are 11203 individuals comprising of 3281 (GSTM1 null 1806) cases of colorectal cancer and 7922(GSTM1 null 3989) healthy controls. A test for heterogeneity between studies showed little evidence of heterogeneity and can be ignored (P= 0.13,12= 27%).Therefore, the fixed-effect model was applied and the result indicated that GSTM1 null genotype was associated with colorectal cancer risk (P=0.0004, OR合并=1.16,95% CI:1.07-1.27;Fig. 6;Table 2).Japanese subgroup included 4 studies,there are 2085 individuals comprising of 960 (GSTMl null 505) cases of colorectal cancer and 1125(GSTM1 null 581) healthy controls. A test for heterogeneity between studies showed little evidence of heterogeneity and can be ignored (P=0.13,I2=47%).Therefore, the fixed-effect model was applied and the result did not indicate any significant association between GSTM1 null genotype and the risk of colorectal cancer in Japanese (P= 0.064, OR合并=1.04,95% CI:0.88-1.24;Fig.6;Table 2).Other countries subgroup included 5 studies.there are 6536 individuals comprising of 3199 (GSTM1 null 1685) cases of colorectal cancer and 3037(GSTM1 null 1551) healthy controls.A test for heterogeneity between studies showed little evidence of heterogeneity and can be ignored (P=0.11,12=47%).Therefore, the fixed-effect model was applied and the result did not indicate any significant association between GSTM1 null genotype and the risk of colorectal cancer in Japanese (P= 0.54, OR 合并=1.03,95% CI:0.93-1.14;Fig.6;Table 2).Sensitivity analysis and Publication BiasEach study was excluded one at a time to determine the magnitude of influence on the overall summary estimate.the estimated ORs were insensitive to the removal of individual studies.But after excluded study"Huang P 2003",the other 28 studies’ heterogeneity were significantly reduced, it implied s that "Huang P 2003"brought great heterogeneity. (Table 3).For assessing Bias,the shape of the funnel plot seems symmetric,it implied no evidence of publication bias.Figure 7 shows the funnel plot(Figure 7).Conclusions:1.The Meta analysis in the Asian population indicated that GSTM1 null was associated with colorectal cancer risk, but the correlation is not obvious.2.In the subgroup analysis of Chinese population indicated that GSTM1 null was associated with colorectal cancer risk, but it did not indicate any significant association between GSTM1 null genotype and the risk of colorectal cancer in Japanese.Case-control study subgroup suggested association between GSTM1 null and colorectal cancer risk. But Cohort study subgroup did not suggest association between GSTM1 null and colorectal cancer risk.3.Due to the heterogeneity between studies, and without considering the interaction between genes and genes or genes and environment,more well-designed and large sample prospective studies should be made to further verification the conclusions in different ethnities. |
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