MSX1 gene polymorphisms and non-syndromic cleft lip with or without palate (NSCL/P): A meta-analysis.

OBJECTIVE: Non-syndromic cleft lip, with or without cleft palate (NSCL/P), is a common craniofacial birth defect, the risk of which is influenced from multiple genetic loci. Association study outcomes between single nucleotide polymorphisms (SNPs) near the muscle segment homeobox gene 1 (MSX1) and NSCL/P have been inconsistent. This compels a meta-analysis to obtain more precise estimates. METHODS: From 15 publications, we examined 12 SNPs under six groups (SG), based on linkage disequilibrium. Pooled odds ratios and 95% confidence intervals were calculated under the standard genetic models. The pooled effects were subjected to subgroup, outlier, sensitivity, and funnel plot (publication bias) analyses. RESULTS: Three of the six SGs showed significant associations. SG1 and SG4 effects indicated reduced risks. SG1 outcomes were attributed to outlier treatment, which the Asian outcomes validated. In contrast, increased risks were observed in SG3. All these significant outcomes were deemed robust by sensitivity analysis with no evidence of publication bias. CONCLUSIONS: Our study shows eight MSX1 SNPs associated with risk of NSCL/P. SG1 and SG4 carriers are protected (up to 23%), but SG3 carriers are 1.3-fold susceptible. Outlier treatment unmasked the significant associations in SG1. Non-heterogeneity and robustness helped elevate the level of evidence in our significant findings.