It is expected that the limited sample size causing serious power-loss. Before making a conclusion on the heterogeneity, power calculations about the meta-analysis should be performed. The power analysis suggested that power of 91% was determined for rs4444903. As shown in Figure s1, http://links.lww.com/MD/C743, our meta-analysis collected 9 studies with 1448 cases. The required information size for this meta-analysis was 4312 with the indexes: type I error (α = 0.05), type II error (β = .2). However, the results of TSA showed the EGF A61G contribute to the risk of CRC was reliable.
Sensitivity analysis which excluded the influence of a single study on the overall risk estimate by excluding 1 study at a time was confirmed. The ORs were significantly altered by excluding Wu et al (Fig. 3). After omitted this study, significant association was only detected between the recessive model of EGF A61G and CRC in Asian population (OR = 1.27, 95% CI [1.05, 1.53], P = .01) (Table s2, http://links.lww.com/MD/C743). Sensitivity analysis based on these 8 studies showed that The ORs were not significantly altered in each genetic models (Fig. s2, http://links.lww.com/MD/C743).
Funnel plots and Egger test were performed to assess publication bias. The results suggested that there was no publication bias for the comparison of EGF A61G in allelic, dominant, and recessive models (Fig. 4).
CRC is a multistep process, where genetic changes occur with mutations of several genes that accumulate with the progression from a normal epithelium to an adenoma to invasive cancer. The EGFR system is an important mediator in the tumor microenvironment that results in enhanced tumor growth. EGF exerts effects on cell proliferation and differentiation by binding to the tyrosine kinase EGF receptor. Both EGF and EGFR expression have been described to be significantly increased in patients with CRC compared with that in the normal individuals. And the impact of EGF polymorphisms on cancers has been described. Recently, it has been shown that EGF A61G has a functional influence on the expression of EGF gene in CRC patients. Subsequently, the genetic association between EGF A61G and CRC was also investigated by several studies with conflicting results.[16–27]
In addition, significant association was also observed between the recessive model (GG/AG + AA) of EGF A61G and CRC in both total group and subgroups stratified by ethnicity, which was partly similar with the results reported by Piao et al. The G/G genotype was reported to lead to a higher production of EGF, and thus increase risk of colorectal cancer. The mechanism that the GG genotype of EGF A61G increases the EGF production may due to the following reasons. First, G to A substitution might affect the DNA folding or processing of the mRNA transcript. Second, this polymorphism might be closely linked to a functional polymorphism elsewhere in the gene.
However, we failed to detect association between the dominant model (GG + AG/AA) of EGF A61G and CRC both in total group and subgroups analysis stratified by ethnicity, which was similar with the results reported by Li et al, but contrast to the results conducted by Piao et al. The inconsistent results in the previous meta-analysis may due to the following reasons. Firstl, the number of included studies in previous meta-analysis studies was relatively small. Although we included 6 more studies to investigate the association between the dominant model of EGF A61G and colorectal cancer, negative results were still obtained. Thus, more studies with larger number of cohorts and multiple ethnicity are still necessary. Second, differences in genetic and environmental background exist among different ethnicity. Third, different populations usually have different linkage disequilibrium patterns.
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