{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T10:33:15Z","timestamp":1791109995406,"version":"4.1.0"},"reference-count":32,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2012,6,22]],"date-time":"2012-06-22T00:00:00Z","timestamp":1340323200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Birth Defects Research"],"published-print":{"date-parts":[[2012,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p><jats:bold>BACKGROUND<\/jats:bold> Oral clefts are common congenital anomalies and result from defects during embryogenesis. The complex etiology is evident by the number of genes and signaling pathways involved in craniofacial development. Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) are responsible for tissue remodeling during craniofacial development. <jats:bold>METHODS<\/jats:bold> In this study, we investigated the association of polymorphisms in 14 biologically relevant MMP and TIMP genes in 494 individuals with oral clefts and 413 control individuals from Brazil. Genotypes were generated using Taqman chemistry. Analyses were performed using PLINK software. <jats:bold>RESULTS<\/jats:bold> Polymorphisms in <jats:italic>MMP3<\/jats:italic> (rs522616) and <jats:italic>TIMP2<\/jats:italic> (rs8179096) showed significant association with all cleft types (all clefts, cleft lip\/palate, and cleft palate; <jats:italic>p<\/jats:italic> \u2264 0.002). An additional family\u2010based dataset (881 case\u2010parent trios) from the United States was used for confirmation of the association findings (<jats:italic>p<\/jats:italic> &lt; 0.05). Analysis of gene\u2010gene interaction suggests that <jats:italic>MMP3<\/jats:italic> and <jats:italic>TIMP2<\/jats:italic> may interactively contribute to a cleft phenotype. <jats:bold>CONCLUSIONS<\/jats:bold> This study provides new evidence that variation in <jats:italic>MMP3<\/jats:italic> may contribute to nonsyndromic oral clefts and further supports the involvement of <jats:italic>TIMP2<\/jats:italic> as a cleft susceptibility gene. Although additional studies are still necessary to unveil the exact mechanism by which <jats:italic>MMP3<\/jats:italic> and <jats:italic>TIMP2<\/jats:italic> would contribute to a cleft phenotype, allelic polymorphisms in these genes and their interactions may partly explain the variance of individual susceptibility to oral clefts. 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