The Common Variant rs4444235 near BMP4 Confers Genetic Susceptibility of Colorectal Cancer: An Updated Meta-Analysis Based on a Comprehensive Statistical Strategy

OBJECTIVE: We performed an updated meta-analysis, using a comprehensive strategy of a logistic regression and a model-free approach, to evaluate more precisely the role of the rs4444235 variant near the Bone morphogenetic protein-4 (BMP4) gene in susceptibility to colorectal cancer (CRC). METHODS: A total of 19 studies with 28770 cases and 28234 controls were included. Metagen system with logistic regression was applied to choose the most plausible genetic model for rs4444235. Generalized odds ratio (OR(G)) metric was used to provide a global test of relationship between rs4444235 and CRC risk. RESULTS: Metagen analysis suggested the rs4444235 fitted best to an additive model. In assessment of the additive model, heterogeneity was observed (P = 0.059, I(2) = 36.1), and pooled per-allele OR was 1.08 (95% CI = 1.05–1.11). Based on the model-free approach, pooled OR(G) was 1.09 (95% CI = 1.05–1.14) under a random-effect model. Stratified analyses suggested heterogeneity could be in part explained by population ethnicity, study design, sources of controls, and sample size. Sensitivity analysis further supported the robust stability of the current results, by showing similar pooled estimates before and after sequential removal of each study. CONCLUSIONS: This meta-analysis provides a robust estimate of the positive association between the rs4444235 and CRC risk and further emphasizes the importance of the rs4444235 in CRC risk prediction.