Association of VAX1, MAFB, WNT3 with Non-Syndromic Cleft Lip with or without Cleft Palate in a Japanese Population

<b>Background/Objectives:</b> Non-syndromic cleft lip with or without palate (NSCL/P) is a common, multifactorial congenital anomaly. As genetic associations can be population-specific, this study aimed to investigate single-nucleotide polymorphisms (SNPs) in the <i>VAX1</i>, <i>MAFB</i>, and <i>WNT3</i> genes for association with NSCL/P in a Japanese cohort. <b>Methods:</b> A case-control study was conducted with 310 Japanese patients with NSCL/P and 308 ethnically matched healthy controls from Aichi Gakuin Dental Hospital. We genotyped SNPs rs7078160 (<i>VAX1</i>), rs13041247 (<i>MAFB</i>), and rs3809857 (<i>WNT3</i>) using TaqMan assays. Associations were assessed using chi-squared tests, with results stratified by sex and corrected for multiple comparisons using the Bonferroni method. <b>Results:</b> The <i>VAX1</i> rs7078160 A allele was significantly associated with an increased risk for NSCL/P (OR = 1.67, <i>p</i> < 0.00001). The association was particularly strong in females (OR = 1.93, <i>p</i> < 0.00001) but not significant in males after correction. The <i>MAFB</i> rs13041247 variant showed a nominal protective association with the NSCLO subtype that was not significant after Bonferroni correction. No significant association was found for <i>WNT3</i>. A notable gene-gene interaction was observed, where carrying risk alleles for both <i>VAX1</i> and <i>MAFB</i> significantly increased overall NSCL/P risk (OR = 2.65, <i>p</i> = 0.00008). <b>Conclusions:</b><i>VAX1</i> rs7078160 is a significant risk factor for NSCL/P in the Japanese population, with a pronounced female-specific effect. A synergistic interaction between <i>VAX1</i> and <i>MAFB</i> elevates disease risk, whereas <i>WNT3</i> was not implicated in this cohort. These findings underscore the population-specific genetic architecture of NSCL/P.