{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,19]],"date-time":"2025-10-19T16:02:11Z","timestamp":1760889731351,"version":"3.40.5"},"reference-count":40,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2018,11,6]],"date-time":"2018-11-06T00:00:00Z","timestamp":1541462400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"The State of Bahia Research Foundation- FAPESB, Bahia, Brazil","award":["2016\/591"],"award-info":[{"award-number":["2016\/591"]}]},{"name":"The State of Minas Gerais Research Foundation- PPM-FAPEMIG","award":["2017\/00312"],"award-info":[{"award-number":["2017\/00312"]}]},{"name":"The State of S\u00e3o Paulo Research Foundation-FAPESP, S\u00e3o Paulo, Brazil","award":["2016\/02667-0"],"award-info":[{"award-number":["2016\/02667-0"]}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Birth Defects Research"],"published-print":{"date-parts":[[2019,1]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>\n<jats:italic>GREM1,<\/jats:italic> which encodes Gremlin 1, an antagonist of bone morphogenic proteins with effects on proliferation and apoptosis, has been considered a candidate gene for nonsyndromic cleft lip with or without cleft palate (NSCL\u00b1P). In this study, we investigated potential associations of single nucleotide polymorphisms (SNP) in <jats:italic>GREM1<\/jats:italic> and NSCL\u00b1P risk in the Brazilian population. Additionally, SNP\u2010SNP interactions of <jats:italic>GREM1<\/jats:italic> with previously reported rs1880646 variant in <jats:italic>NTN1<\/jats:italic> (netrin 1), a gene also responsible for apoptotic phenotypes were verified.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Applying Taqman allelic discrimination assays, we evaluated the variants rs16969681, rs16969816, rs16969862, and rs1258763 in 325 case\u2010parent trios and in 1,588 isolated samples in a case\u2010control study. Allelic and genotypic analyses, as well as interaction tests assessing gene\u2010environmental factor (GxE) and SNP\u2010SNP interaction with rs1880646 variant in <jats:italic>NTN1<\/jats:italic>, were performed based on logistic regression analysis adjusted for the effects of gender and genomic ancestry proportions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The risk alleles of all SNP were undertransmitted in NSCL\u00b1P trios, though the case\u2010control analysis confirmed only the association with rs16969862 alleles (OR: 0.78, 95% CI: 0.63\u20130.96, <jats:italic>p<\/jats:italic>\u2009=\u2009.02). The GxE interaction analysis revealed a significant interaction between maternal environmental contact with agrotoxics and rs16969816 (OR: 0.25, 95% CI: 0.08\u20130.74, <jats:italic>p<\/jats:italic>\u2009=\u2009.01), and pairwise interaction test with <jats:italic>NTN1<\/jats:italic> rs1880646 yielded significant <jats:italic>p<\/jats:italic> values in the 1,000 permutation test for rs16969681, rs16969816, and rs16969862.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The <jats:italic>GREM1<\/jats:italic> is involved in the etiology of NSCL\u00b1P in the Brazilian population and reveal that the interaction between <jats:italic>GREM1<\/jats:italic> and <jats:italic>NTN1<\/jats:italic> may be related with the pathogenesis of this common craniofacial malformation.<\/jats:p><\/jats:sec>","DOI":"10.1002\/bdr2.1405","type":"journal-article","created":{"date-parts":[[2018,11,7]],"date-time":"2018-11-07T04:24:52Z","timestamp":1541564692000},"page":"16-25","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Understanding the participation of <i>GREM1<\/i> polymorphisms in nonsyndromic cleft lip with or without cleft palate in the Brazilian population"],"prefix":"10.1002","volume":"111","author":[{"given":"Camila Sane","family":"Viena","sequence":"first","affiliation":[{"name":"Basic Science Department, Area of Oral Pathology Bahiana School of Medicine and Public Health  Salvador Bahia Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Renato Assis","family":"Machado","sequence":"additional","affiliation":[{"name":"Department of Oral Diagnosis, School of Dentistry University of Campinas  Piracicaba S\u00e3o Paulo Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Darlene Camati","family":"Persuhn","sequence":"additional","affiliation":[{"name":"Molecular Biology Department Federal University of Para\u00edba  Jo\u00e3o Pessoa Para\u00edba Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Herc\u00edlio","family":"Martelli\u2010J\u00fanior","sequence":"additional","affiliation":[{"name":"Stomatology Clinic, Dental School State University of Montes Claros  Montes Claros Minas Gerais Brazil"},{"name":"Center for Rehabilitation of Craniofacial Anomalies, Dental School University of Jos\u00e9 Ros\u00e1rio Vellano  Minas Gerais Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alena Peixoto","family":"Medrado","sequence":"additional","affiliation":[{"name":"Basic Science Department, Area of Oral Pathology Bahiana School of Medicine and Public Health  Salvador Bahia Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5285-3046","authenticated-orcid":false,"given":"Ricardo D.","family":"Coletta","sequence":"additional","affiliation":[{"name":"Department of Oral Diagnosis, School of Dentistry University of Campinas  Piracicaba S\u00e3o Paulo Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1195-0485","authenticated-orcid":false,"given":"Silvia R. 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