{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:59:48Z","timestamp":1785416388445,"version":"3.56.0"},"reference-count":31,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T00:00:00Z","timestamp":1753142400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JSPS KAKENHI","award":["23K09325"],"award-info":[{"award-number":["23K09325"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Non-syndromic orofacial clefts (NSOFCs) are one of the common congenital malformations in Vietnam, with 1.4 per 1000 live births, with notable sex differences in occurrence. This case\u2013control study aims to investigate potential sex-specific interactions of WNT3 and NOG polymorphisms across NSOFC subtypes in a Vietnamese population. Methods: A total of 720 participants were separated into 4 groups with a male\/female ratio of 1:1 (160 individuals with cleft lip and palate (NSCLP), 160 with cleft lip only (NSCLO), 160 with cleft palate only (NSCPO), 240 healthy controls). Two single-nucleotide polymorphisms (SNPs), rs3809857 and rs227731, were genotyped by using the StepOnePlus Real-Time PCR System. Results: The most significant findings were found in the male NSCLO group under a recessive model of WNT3 rs3809857 after applying Bonferroni correction, as a five-fold protective factor with OR = 0.18 (95% confidence interval: 0.05\u20130.64, p = 0.0033). Additionally, the weak or moderate protective association between rs3809857 and male NSCLP was found with p &lt; 0.05 under the dominant model. However, there were no significant findings in the female NSOFC subtypes associated with WNT3. Conversely, NOG rs227731 results showed a weak increased risk in female NSCLO and NSCPO with p &lt; 0.05. Conclusion: this study identified the critical role of WNT3 rs3809857 in reducing NSCLO risk in males. These findings support the potential influence of sex as a modifying factor in the genetic susceptibility to non-syndromic orofacial clefts.<\/jats:p>","DOI":"10.3390\/genes16080853","type":"journal-article","created":{"date-parts":[[2025,7,23]],"date-time":"2025-07-23T11:52:47Z","timestamp":1753271567000},"page":"853","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Gene-Sex Interaction in Non-Syndromic Orofacial Cleft Subtypes: A Case-Control Study Among the Vietnamese Population"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-7872-9291","authenticated-orcid":false,"given":"Le Kha","family":"Anh","sequence":"first","affiliation":[{"name":"Division of Research and Treatment for Oral Maxillofacial Congenital Anomalies, Aichi Gakuin University, Nagoya 464-8651, Japan"},{"name":"School of Dentistry, Hanoi Medical University, Hanoi 10000, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teruyuki","family":"Niimi","sequence":"additional","affiliation":[{"name":"Division of Research and Treatment for Oral Maxillofacial Congenital Anomalies, Aichi Gakuin University, Nagoya 464-8651, Japan"},{"name":"Cleft Lip and Plate Center, Aichi Gakuin University Dental Hospital, Nagoya 464-8651, Japan"},{"name":"Division of Speech, Hearing, and Language, Aichi Gakuin University Dental Hospital, Nagoya 464-8651, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Division of Research and Treatment for Oral Maxillofacial Congenital Anomalies, Aichi Gakuin University, Nagoya 464-8651, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4060-1356","authenticated-orcid":false,"given":"Toko","family":"Hayakawa","sequence":"additional","affiliation":[{"name":"Cleft Lip and Plate Center, Aichi Gakuin University Dental Hospital, Nagoya 464-8651, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken","family":"Kitagawa","sequence":"additional","affiliation":[{"name":"Division of Research and Treatment for Oral Maxillofacial Congenital Anomalies, Aichi Gakuin University, Nagoya 464-8651, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chisato","family":"Sakuma","sequence":"additional","affiliation":[{"name":"Division of Research and Treatment for Oral Maxillofacial Congenital Anomalies, Aichi Gakuin University, Nagoya 464-8651, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideto","family":"Imura","sequence":"additional","affiliation":[{"name":"Division of Research and Treatment for Oral Maxillofacial Congenital Anomalies, Aichi Gakuin University, Nagoya 464-8651, Japan"},{"name":"Cleft Lip and Plate Center, Aichi Gakuin University Dental Hospital, Nagoya 464-8651, Japan"},{"name":"Division of Speech, Hearing, and Language, Aichi Gakuin University Dental Hospital, Nagoya 464-8651, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7373-9282","authenticated-orcid":false,"given":"Hisataka","family":"Kondo","sequence":"additional","affiliation":[{"name":"Junior College, Aichi Gakuin University, Nagoya 464-0037, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nguyen Huu","family":"Tu","sequence":"additional","affiliation":[{"name":"Department of Anesthesia-Resuscitation, Hanoi Medical University, Hanoi 10000, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong Minh","family":"Son","sequence":"additional","affiliation":[{"name":"School of Dentistry, Hanoi Medical University, Hanoi 10000, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vo Truong Nhu","family":"Ngoc","sequence":"additional","affiliation":[{"name":"School of Dentistry, Hanoi Medical University, Hanoi 10000, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tran Phuong","family":"Thao","sequence":"additional","affiliation":[{"name":"Division of Research and Treatment for Oral Maxillofacial Congenital Anomalies, Aichi Gakuin University, Nagoya 464-8651, Japan"},{"name":"School of Dentistry, Hanoi Medical University, Hanoi 10000, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nguyen Minh","family":"Duc","sequence":"additional","affiliation":[{"name":"Division of Research and Treatment for Oral Maxillofacial Congenital Anomalies, Aichi Gakuin University, Nagoya 464-8651, Japan"},{"name":"School of Dentistry, Hanoi Medical University, Hanoi 10000, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pham Nguyen Gia","family":"Loc","sequence":"additional","affiliation":[{"name":"Division of Research and Treatment for Oral Maxillofacial Congenital Anomalies, Aichi Gakuin University, Nagoya 464-8651, Japan"},{"name":"Odonto-Maxillo Facial Hospital of Ho Chi Minh City, Ho Chi Minh City 71000, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroo","family":"Furukawa","sequence":"additional","affiliation":[{"name":"Division of Speech, Hearing, and Language, Aichi Gakuin University Dental Hospital, Nagoya 464-8651, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nagana","family":"Natsume","sequence":"additional","affiliation":[{"name":"Division of Research and Treatment for Oral Maxillofacial Congenital Anomalies, Aichi Gakuin University, Nagoya 464-8651, Japan"},{"name":"Cleft Lip and Plate Center, Aichi Gakuin University Dental Hospital, Nagoya 464-8651, Japan"},{"name":"Division of Speech, Hearing, and Language, Aichi Gakuin University Dental Hospital, Nagoya 464-8651, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nagato","family":"Natsume","sequence":"additional","affiliation":[{"name":"Division of Research and Treatment for Oral Maxillofacial Congenital Anomalies, Aichi Gakuin University, Nagoya 464-8651, Japan"},{"name":"Cleft Lip and Plate Center, Aichi Gakuin University Dental Hospital, Nagoya 464-8651, Japan"},{"name":"Division of Speech, Hearing, and Language, Aichi Gakuin University Dental Hospital, Nagoya 464-8651, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.1016\/S0140-6736(09)60695-4","article-title":"Cleft lip and palate","volume":"374","author":"Mossey","year":"2009","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1038\/nrg2933","article-title":"Cleft lip and palate: Understanding genetic and environmental influences","volume":"12","author":"Dixon","year":"2011","journal-title":"Nat. Rev. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1597\/1545-1569_1998_035_0183_tte_2.3.co_2","article-title":"In Vietnam, many congenital anomalies are believed to result from the scattering of defoliants, including dioxin","volume":"35","author":"Natsume","year":"1998","journal-title":"Cleft Palate Craniofac. J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"109598","DOI":"10.1016\/j.ijporl.2019.109598","article-title":"The impact of cleft lip and\/or palate on parental quality of life: A pilot study","volume":"126","author":"Dochy","year":"2019","journal-title":"Int. J. Pediatr. Otorhinolaryngol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1146\/annurev-genom-090711-163729","article-title":"The Evolution of Human Genetic Studies of Cleft Lip and Cleft Palate","volume":"13","author":"Marazita","year":"2012","journal-title":"Annu. Rev. Genom. Hum. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1177\/00220345211046614","article-title":"Genome-wide Gene-by-Sex Interaction Studies Identify Novel Nonsyndromic Orofacial Clefts Risk Locus","volume":"101","author":"Awotoye","year":"2021","journal-title":"J. Dent. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1002\/gepi.22158","article-title":"Genome-wide interaction studies identify sex-specific risk alleles for nonsyndromic orofacial clefts","volume":"42","author":"Carlson","year":"2018","journal-title":"Genet. Epidemiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1111\/cga.12259","article-title":"Association of MEOX2 polymorphism with nonsyndromic cleft palate only in a Vietnamese population","volume":"58","author":"Tran","year":"2018","journal-title":"Congenit. Anom."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1002\/dvdy.22072","article-title":"Visualizing canonical Wnt signaling during mouse craniofacial development","volume":"239","author":"Mani","year":"2010","journal-title":"Dev. Dynam."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1177\/1055665617732782","article-title":"Association of WNT Pathway Genes with Nonsyndromic Cleft Lip with or Without Cleft Palate","volume":"55","author":"Vijayan","year":"2018","journal-title":"Cleft Palate Craniofac. J."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Marchini, M., Hu, D., Lo Vercio, L., Young, N.M., Forkert, N.D., Hallgr\u00edmsson, B., and Marcucio, R. (2021). Wnt Signaling Drives Correlated Changes in Facial Morphology and Brain Shape. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.644099"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1016\/j.devcel.2011.08.005","article-title":"A Conserved Pbx-Wnt-p63-Irf6 Regulatory Module Controls Face Morphogenesis by Promoting Epithelial Apoptosis","volume":"21","author":"Ferretti","year":"2011","journal-title":"Dev. Cell."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1002\/bdr2.1630","article-title":"PBX-WNT-P63-IRF6 pathway in nonsyndromic cleft lip and palate","volume":"112","author":"Maili","year":"2020","journal-title":"Birth. Defects. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1002\/bdra.20430","article-title":"Mouse genetic models of cleft lip with or without cleft palate","volume":"82","author":"Juriloff","year":"2008","journal-title":"Birth. Defects. Res. A Clin. Mol. Teratol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1448","DOI":"10.1002\/dvdy.20723","article-title":"Expression of Wnt9b and activation of canonical Wnt signaling during midfacial morphogenesis in mice","volume":"235","author":"Lan","year":"2006","journal-title":"Dev. Dyn."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.ydbio.2010.08.014","article-title":"Modulation of BMP signaling by Noggin is required for the maintenance of palatal epithelial integrity during palatogenesis","volume":"347","author":"He","year":"2010","journal-title":"Dev. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/ng.506","article-title":"Genome-wide association study identifies two susceptibility loci for nonsyndromic cleft lip with or without cleft palate","volume":"42","author":"Mangold","year":"2010","journal-title":"Nat. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1002\/bdra.23612","article-title":"Associations between the NOGGIN rs227731 polymorphism and NSCL\/P risk may be associated with ethnicities: A meta-analysis","volume":"109","author":"Wang","year":"2017","journal-title":"Birth. Defects. Res."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Wang, B.Q., Gao, S.T., Chen, K., Xu, Z.Q., Sun, J.M., Xia, Y., and Lv, Z.T. (2018). Association of the WNT3 polymorphisms and non-syndromic cleft lip with or without cleft palate: Evidence from a meta-analysis. Biosci. Rep., 38.","DOI":"10.1042\/BSR20181676"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1038\/nature15393","article-title":"A global reference for human genetic variation","volume":"526","author":"Auton","year":"2015","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1016\/j.ijporl.2007.06.007","article-title":"Human genetic factors in nonsyndromic cleft lip and palate: An update","volume":"71","author":"Carinci","year":"2007","journal-title":"Int. J. Pediatr. Otorhinolaryngol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1002\/bdra.20720","article-title":"Studies with Wnt genes and nonsyndromic cleft lip and palate","volume":"88","author":"Menezes","year":"2010","journal-title":"Birth. Defects. Res. A Clin. Mol. Teratol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"12646","DOI":"10.4238\/2015.October.19.8","article-title":"Variations in WNT3 gene are associated with incidence of non-syndromic cleft lip with or without cleft palate in a northeast Chinese population","volume":"14","author":"Lu","year":"2015","journal-title":"Genet. Mol. Res."},{"key":"ref_24","first-page":"168","article-title":"Association of the WNT3 Variations and the Risk of Non-Syndromic Cleft Lip and Palate in a Population of Iranian Infants","volume":"10","author":"Masoudian","year":"2018","journal-title":"Avicenna. J. Med. Biotechnol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Zawi\u015blak, A., Wo\u017aniak, K., Tartaglia, G., Agirre, X., Gupta, S., Kawala, B., Znamirowska-Bajowska, A., Grocholewicz, K., Prosper, F., and Lubi\u0144ski, J. (2024). Single-Nucleotide Polymorphisms in WNT Genes in Patients with Non-Syndromic Orofacial Clefts in a Polish Population. Diagnostics, 14.","DOI":"10.3390\/diagnostics14141537"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Wu, W., Gu, S., Sun, C., He, W., Xie, X., Li, X., Ye, W., Qin, C., Chen, Y., and Xiao, J. (2015). Altered FGF Signaling Pathways Impair Cell Proliferation and Elevation of Palate Shelves. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0136951"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3267","DOI":"10.1002\/ajmg.a.32098","article-title":"X-chromosome inactivation patterns in monozygotic twins and sib pairs discordant for nonsyndromic cleft lip and\/or palate","volume":"143","author":"Kimani","year":"2007","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1002\/bdra.22862","article-title":"Polymorphic variants at 10q25.3 and 17q22 loci and the risk of non-syndromic cleft lip and palate in the polish population","volume":"94","author":"Mostowska","year":"2012","journal-title":"Birth. Defects. Res. A Clin. Mol. Teratol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1097\/01.GIM.0000127275.52925.05","article-title":"In a Vietnamese population, MSX1 variants contribute to cleft lip and palate","volume":"6","author":"Suzuki","year":"2004","journal-title":"Genet. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e1754","DOI":"10.1002\/mgg3.1754","article-title":"Family based and case\u2013control designs reveal an association of TFAP2A in nonsyndromic cleft lip only among Vietnamese population","volume":"9","author":"Nguyen","year":"2021","journal-title":"Mol. Genet. Genomic Med."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Pham, L.N.G., Niimi, T., Suzuki, S., Nguyen, M.D., Nguyen, L.C.H., Nguyen, T.D., Hoang, K.A., Nguyen, D.M., Sakuma, C., and Hayakawa, T. (2023). Association between IRF6, TP63, GREM1 Gene Polymorphisms and Non-Syndromic Orofacial Cleft Phenotypes in Vietnamese Population: A Case-Control and Family-Based Study. Genes, 14.","DOI":"10.3390\/genes14111995"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/8\/853\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:14:13Z","timestamp":1760033653000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/8\/853"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,22]]},"references-count":31,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["genes16080853"],"URL":"https:\/\/doi.org\/10.3390\/genes16080853","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,22]]}}}