Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Jul 24;16(8):862.
doi: 10.3390/genes16080862.

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

Tran Phuong Thao  1   2 , Teruyuki Niimi  1   3   4 , Satoshi Suzuki  1 , Toko Hayakawa  3 , Chisato Sakuma  1 , Ken Kitagawa  1 , Hideto Imura  1   3   4 , Hisataka Kondo  5 , Nguyen Huu Tu  6 , Tong Minh Son  2 , Vo Truong Nhu Ngoc  2 , Le Kha Anh  1   2 , Pham Nguyen Gia Loc  1   7 , Hiroo Furukawa  4 , Nagana Natsume  1   3   4 , Nagato Natsume  1   3   4
Affiliations

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

Tran Phuong Thao et al. Genes (Basel). .

Abstract

Background/Objectives: 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 VAX1, MAFB, and WNT3 genes for association with NSCL/P in a Japanese cohort. Methods: 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 (VAX1), rs13041247 (MAFB), and rs3809857 (WNT3) using TaqMan assays. Associations were assessed using chi-squared tests, with results stratified by sex and corrected for multiple comparisons using the Bonferroni method. Results: The VAX1 rs7078160 A allele was significantly associated with an increased risk for NSCL/P (OR = 1.67, p < 0.00001). The association was particularly strong in females (OR = 1.93, p < 0.00001) but not significant in males after correction. The MAFB rs13041247 variant showed a nominal protective association with the NSCLO subtype that was not significant after Bonferroni correction. No significant association was found for WNT3. A notable gene-gene interaction was observed, where carrying risk alleles for both VAX1 and MAFB significantly increased overall NSCL/P risk (OR = 2.65, p = 0.00008). Conclusions:VAX1 rs7078160 is a significant risk factor for NSCL/P in the Japanese population, with a pronounced female-specific effect. A synergistic interaction between VAX1 and MAFB elevates disease risk, whereas WNT3 was not implicated in this cohort. These findings underscore the population-specific genetic architecture of NSCL/P.

Keywords: Japanese population; MAFB; VAX1; WNT3; cleft lip with or without palate.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Forest plots of odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between genotypes of VAX1 rs7078160, MAFB rs13041247, and WNT3 rs3809857 with NSCL/P and its subtypes. Significant associations were observed for VAX1 genotypes.
Figure 2
Figure 2
Forest plots of odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between genotypes of VAX1 rs7078160, MAFB rs13041247, and WNT3 rs3809857 with NSCL/P and its subtypes in females. Significant associations were observed for VAX1 genotypes.
Figure 3
Figure 3
Forest plots of odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between genotypes of VAX1 rs7078160, MAFB rs13041247, and WNT3 rs3809857 with NSCL/P and its subtypes in males.
See this image and copyright information in PMC

References

    1. Cooper M.E., Ratay J.S., Marazita M.L. Asian Oral-Facial Cleft Birth Prevalence. Cleft Palate Craniofac. J. 2006;43:580–589. doi: 10.1597/05-167. - DOI - PubMed
    1. Wornom I.L., Will L.A., Burdi A.R., Berkowitz S., Breen M.L., Clarke-Sheehan N., Curtin V.M., D’Antonio L.L., Friedman C.D., Gleason A.T., et al. Core Curriculum for Cleft Lip/Palate and other Craniofacial Anomalies. In: Berkowitz S., editor. Cleft Lip and Palate. Springer; Berlin/Heidelberg, Germany: 2006. pp. 285–300. - DOI
    1. Dixon M.J., Marazita M.L., Beaty T.H., Murray J.C. Cleft lip and palate: Understanding genetic and environmental influences. Nat. Rev. Genet. 2011;12:167–178. doi: 10.1038/nrg2933. - DOI - PMC - PubMed
    1. Yoshida K., Natsume N., Kinoshita H., Tsunoda N., Takahashi H., Kawai T. Experimental Study on Cleft Lip and/or Palate: Fetuses of A/J Mice in Uteri of F1 Hybrid Mothers Using Ovarian Transplantation. Cleft Palate Craniofac. J. 1996;33:291–296. doi: 10.1597/1545-1569_1996_033_0291_esocla_2.3.co_2. - DOI - PubMed
    1. Kuno J., Natsume N., Kawai T. Transplantation of Fertilized Ova of cleft lip and palate-Resistant C57BL/6 Strain Mice to Pseudopregnant cleft lip and palate-Prone A/J Strain Mice. Plast. Reconstr. Surg. 2000;105:2625–2626. doi: 10.1097/00006534-200006000-00063. - DOI - PubMed

Supplementary concepts

Grants and funding

LinkOut - more resources