DISCUSSION


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A stratified analysis by leukemia type and ethnic group was conducted in this study in order to clarify the role of the XRCC1 Arg399Gln SNP in the development of four types of leukemia in different ethnic groups. Twenty-three studies were identified wherein research into the association between XRCC1Arg399Gln SNP and different types of leukemia risk was conducted. Conclusions among these studies were not consistent, indicating an urgent need for the development of a systematic method for drawing more precise conclusions. Therefore, a common method of systematic review, a meta-analysis, was conducted in the present study to integrate these apparently contradictory findings with a view to yielding more accurate results. All of the included articles were of high quality and presented a rigorous scientific design, accurate data reporting, and clear results. The main conclusion was that the presence of the XRCC1 Arg399Gln SNP increased the risk of childhood ALL among Asians. No association was found between this SNP and either CML or CLL risk in Caucasians.

These conclusions suggest the existence of ethnic differences in childhood ALL, such that gene polymorphisms could result in ethnic-specific susceptibilities to leukemia.29 In addition, environmental factors such as birthplace and socioeconomic status may play critical roles in the genesis of leukemia.30 These factors might help to explain the reasons for the observed racial disparities.

The present findings suggest that the risk of childhood ALL is associated with DNA repair mechanisms. The XRCC1 Arg399Gln SNP may be useful as an important predictive factor, and ethnic background may have an impact on the role of this polymorphism on childhood ALL. This SNP may help to identify individuals at risk of developing ALL and represents an essential source of information for improvements in the treatment of ALL treatment.

The presence of heterogeneity between studies must be borne in mind when interpreting the results of a meta-analysis.31,32 Significant heterogeneity existed in the ALL group under the dominant model. After subgroup analyses by ethnicity, the heterogeneity decreased for Asian and Caucasian populations, but persisted in the mixed-race analysis, suggesting that ethnicity can account for the heterogeneity.

The meta-analysis for AML revealed no association between the SNP and risk of AML when random-effects modeling was performed. After excluding the study of Banescu et al,9 an outlier that caused high heterogeneity for the analysis of AML, the fixed-effects modeling, was used for the recessive model, and we found a changed result that the SNP was associated with AML risk in this genetic model, suggesting that the association between the SNP and risk of AML was sensitive to the data from the study of Banescu et al.9 In addition, the sample size for AML was small. Therefore, large-scale studies should be conducted in the future for more explicit and convincing results.

No association was found between the SNP and risk of either CML or CLL in Caucasians. It can be speculated that the development of chronic disease is greatly influenced by environmental factors, and that the influence of SNP might be weak. Accumulation of disadvantageous environmental factors might be required to develop chronic disease. Therefore, a study of environment–genetic interactions would be meaningful for this kind of chronic disease. Smoking and alcohol consumption are also important risk factors for leukemia.33 Although in the present study we endeavored to extract relevant information regarding smoking and drinking from the primary literature, insufficient data were obtained. Further investigations concerning the interactions between smoking, drinking, and gene variations with CLL and CML are required.

Only Caucasian subjects were included in the meta-analyses with respect to AML, CML, and CLL; therefore, the association between the SNP and risks of AML, CML, and CLL among other races needs to be determined in the future.

A meta-analysis similar to that presented herein was performed by Huang et al in 2014,1 who investigated the associations between XRCC1 Arg399Gln variations and leukemia susceptibility. However, one problem with the meta-analysis was that it was compromised by the inclusion of the study of Ozdemir et al,34 whose cohort comprised both ALL and Burkitt lymphoma patients who were not analyzed separately. Huang et al1 included the combined ALL and Burkitt lymphoma data of Ozdemir et al34 in their pooled ALL data, thus potentially yielding biased results. The study of Ozdemir et al34 was excluded from the present meta-analysis, which also included a greater number of studies than did the meta-analysis performed by Huang et al.1 In particular, the present meta-analysis of ALL included eleven articles, whereas Huang et al1 included only eight. The present statistically significant findings might, therefore, be more accurate than those of Huang et al.1

Two limitations of this meta-analysis should be considered when interpreting its findings. First, the number of eligible studies for the meta-analysis was small, and the results should thus be treated with caution. Further, this restricted the performance of the subgroup analyses. Second, only published studies were included in this meta-analysis. There is always a certain degree of publication bias, and nonsignificant or negative findings may be unpublished and thus underrepresented in the literature.