Association between matrix metalloproteinase 9 polymorphisms and breast cancer risk: An updated meta-analysis and trial sequential analysis

Background: Numerous studies have sought associations between matrix metalloproteinase 9 (MMP-9) polymorphisms and breast cancer risk. However, these studies have yielded conflicting results. Hence, we performed an updated meta-analysis to clarify the effects of four MMP-9 gene polymorphisms (rs3918242, rs2250889, rs3787268, and rs17576) on breast cancer risk. Methods: A comprehensive literature search for eligible studies was conducted in five electronic databases, including PubMed, Embase and Web of Science, up to March 1, 2020. Summary odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations in random-effects models. For the reduction of type I errors, a trial sequential analysis (TSA) was performed. Results: Twenty-one studies (8813 breast cancer cases and 9323 controls) were included in the quantitative analysis. For rs3918242, the overall ORs were significant under allelic comparison (OR (A vs. G) = 1.34; 95% CI 1.03, 1.74, P = 0.028) and the recessive genetic model (OR (AA vs. GG+GA) = 1.40; 95% CI 1.06, 1.84, P = 0.016). For rs2250889, the ORs were significant under homozygote comparison (OR (GG vs. CC) = 2.57; 95% CI 1.22, 5.42, P = 0.013), heterozygote comparison (OR (GC vs. CC) = 2.48; 95% CI 1.17, 5.23, P = 0.018), and the dominant genetic model (OR (GG+GC vs. CC) = 2.53; 95% CI 1.23, 5.20, P = 0.012). No associations were observed for rs3787268 or rs17576. The subgroup analyses indicated that the risk effect of the rs3918242 A allele was observed only among Asians. TSA showed that the findings for rs3918242, rs3787268, and rs17576 were robust, but many more patients are needed before definitive conclusions can be made for rs2250889. Conclusion: Our meta-analysis suggests that MMP-9 rs3918242, but not rs3787268 and rs17576 polymorphisms, may be risk factors for breast cancer. The effect of rs2250889 needs further confirmation with a larger sample size.