{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T20:56:03Z","timestamp":1791665763936,"version":"4.3.4"},"reference-count":40,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,4,7]],"date-time":"2025-04-07T00:00:00Z","timestamp":1743984000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Council for Scientific and Technological Development-CNPq","award":["#402994\/2023-0"],"award-info":[{"award-number":["#402994\/2023-0"]}]},{"name":"National Council for Scientific and Technological Development-CNPq","award":["# APQ-00961-22"],"award-info":[{"award-number":["# APQ-00961-22"]}]},{"name":"National Council for Scientific and Technological Development-CNPq","award":["# RED-00073-23"],"award-info":[{"award-number":["# RED-00073-23"]}]},{"name":"Minas Gerais State Research Foundation-FAPEMIG","award":["#402994\/2023-0"],"award-info":[{"award-number":["#402994\/2023-0"]}]},{"name":"Minas Gerais State Research Foundation-FAPEMIG","award":["# APQ-00961-22"],"award-info":[{"award-number":["# APQ-00961-22"]}]},{"name":"Minas Gerais State Research Foundation-FAPEMIG","award":["# RED-00073-23"],"award-info":[{"award-number":["# RED-00073-23"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Nonsyndromic cleft lip with or without cleft palate (NSCL \u00b1 P) is strongly associated with both environmental and genetic risk factors, but its genetic underpinnings remain partially known. While variants in interferon regulatory factor 6 (IRF6) are linked to NSCL \u00b1 P risk in populations from Asia and Europe, studies on the highly admixed Brazilian population are scarce and have produced ambiguous results. This study aimed to investigate the contribution of IRF6 variants to the risk of NSCL \u00b1 P. Five tag-single nucleotide polymorphisms (rs599021, rs2073485, rs2235375, rs7552506, and rs642961) were analyzed in a large multicenter cohort composed of 1006 patients with NSCL \u00b1 P and 942 healthy controls. Statistical analyses involved multiple logistic regression tests consideration the tri-hybrid genetic origin of the Brazilian population, under a Bonferroni p value correcting for multiple comparisons. The A allele (OR: 1.43, 95% CI: 1.22\u20131.67, p &lt; 0.0001) and AA genotype (OR: 2.04, 95% CI: 1.46\u20132.86, p &lt; 0.0001) frequencies of rs642961 were significantly associated with NSCL \u00b1 P risk. Stratified analyses indicated that the variant is associated with susceptibility to both nonsyndromic cleft lip only (NSCLO) and nonsyndromic cleft lip and palate (NSCLP). However, the association with NSCLO was primarily observed in patients with high African ancestry, whereas the association with NSCLP was predominantly seen in patients with high European ancestry. No significant associations were found for the other investigated variants. Our results support the notion that the IRF6 rs642961 variant represents a marker of susceptibility to NSCL \u00b1 P in the Brazilian population, and that genetic ancestry composition plays a central role in the association with the cleft type.<\/jats:p>","DOI":"10.3390\/ijms26073441","type":"journal-article","created":{"date-parts":[[2025,4,7]],"date-time":"2025-04-07T11:24:39Z","timestamp":1744025079000},"page":"3441","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A Large Multicenter Brazilian Case-Control Study Exploring Genetic Variations in Interferon Regulatory Factor 6 and the Risk of Nonsyndromic Cleft Lip With or Without Cleft Palate"],"prefix":"10.3390","volume":"26","author":[{"given":"Renato Assis","family":"Machado","sequence":"first","affiliation":[{"name":"Department of Oral Diagnosis and Graduate Program in Oral Biology, School of Dentistry, University of Campinas, Piracicaba 13414-018, S\u00e3o Paulo, Brazil"},{"name":"Master Program, School of Dentistry, Ing\u00e1 University Center, Maring\u00e1 87035-510, Paran\u00e1, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3979-7497","authenticated-orcid":false,"given":"Daniella Reis Barbosa","family":"Martelli","sequence":"additional","affiliation":[{"name":"Primary Care\/Health Sciences Postgraduate Program, State University of Montes Claros, Montes Claros 39401-089, Minas Gerais, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia Regina de Almeida","family":"Reis","sequence":"additional","affiliation":[{"name":"Department of Basic Science, Bahiana School of Medicine and Public Health, Salvador 40290-000, Bahia, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2969-1963","authenticated-orcid":false,"given":"Luiz Evaristo","family":"Ricci Volpato","sequence":"additional","affiliation":[{"name":"Postgraduate Program in Integrated Dental Sciences, Cuiaba School of Dentistry, University of Cuiaba, Cuiaba 78000-000, Mato Gosso, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4911-6413","authenticated-orcid":false,"given":"Rafaela","family":"Scariot","sequence":"additional","affiliation":[{"name":"Department of Stomatology, Federal University of Paran\u00e1, Curitiba 80120-170, Parana, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9969-3721","authenticated-orcid":false,"given":"Juliana","family":"Feltrin-Souza","sequence":"additional","affiliation":[{"name":"Department of Stomatology, Federal University of Paran\u00e1, Curitiba 80120-170, Parana, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1080-358X","authenticated-orcid":false,"given":"Ana L\u00facia Carrinho Ayroza","family":"Rangel","sequence":"additional","affiliation":[{"name":"Center of Biological Sciences and of the Health, School of Dentistry, State University of Western Paran\u00e1, Cascavel 85819-110, Paran\u00e1, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Brazilian Oral Cleft Group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herc\u00edlio","family":"Martelli-J\u00fanior","sequence":"additional","affiliation":[{"name":"Primary Care\/Health Sciences Postgraduate Program, State University of Montes Claros, Montes Claros 39401-089, Minas Gerais, Brazil"},{"name":"Center for Rehabilitation of Craniofacial Anomalies, Dental School, University of Jos\u00e9 Rosario Vellano (Unifenas), Alfenas 37130-000, Minas Gerais, Brazil"},{"name":"Oral Pathology and Oral Medicine, Dental School, State University of Montes Claros, Montes Claros 39401-089, Minas Gerais, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5285-3046","authenticated-orcid":false,"given":"Ricardo D.","family":"Coletta","sequence":"additional","affiliation":[{"name":"Department of Oral Diagnosis and Graduate Program in Oral Biology, School of Dentistry, University of Campinas, Piracicaba 13414-018, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.1111\/odi.14174","article-title":"Revisiting the embryogenesis of lip and palate development","volume":"28","author":"Hammond","year":"2022","journal-title":"Oral Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1111\/odi.14238","article-title":"Orofacial clefts: A compendium on non-syndromic cleft lip-cleft 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