Association of Genetic Polymorphism of VAX1 (rs7078160 and rs4752028) with Non-Syndromic Oral Clefts: A Systematic Review and Meta-Analysis

Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a prevalent craniofacial anomaly influenced by genetic and environmental factors. The VAX1 gene is crucial in craniofacial development, and its polymorphisms may contribute to the risk of NSCL/P.

A systematic review and meta-analysis of case–control studies was performed to evaluate the association of VAX1 polymorphisms (rs7078160 and rs4752028) with NSCL/P. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated under different genetic models. Subgroup, sensitivity, and publication bias analyses were also conducted.

Seven studies comprising 1,483 cases and 1,519 controls were identified and included. For rs7078160, individuals with the AA genotype (homozygous for adenine) had a higher NSCL/P risk compared with GG genotype (homozygous for guanine) (OR = 2.34, 95% CI: 1.55–3.24), and AG carriers (heterozygous for adenine and guanine) were also at increased risk (OR = 1.31, 95% CI: 1.11–1.54). For rs4752028, CC (homozygous for cytosine) vs. TT (homozygous for thymine) (OR = 1.47, 95% CI: 1.09–1.97) and CT (heterozygous for cytosine and thymine) vs. TT (OR = 1.28, 95% CI: 1.01–1.52) were significantly associated with NSCL/P. Subgroup analyses showed stronger associations in non-Chinese populations, while results in Chinese cohorts were less consistent. Sensitivity analyses confirmed robustness for rs7078160, but funnel plot and Egger’s test indicated potential publication bias for rs4752028 (p=0.044).

VAX1 rs7078160 and rs4752028 polymorphisms are significantly associated with increased NSCL/P risk, particularly among non-Chinese populations. Further large-scale multi-ethnic studies considering gene–environment interactions are warranted to validate these findings.