{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T14:32:49Z","timestamp":1747146769537,"version":"3.40.5"},"reference-count":47,"publisher":"Wiley","issue":"20","license":[{"start":{"date-parts":[[2021,10,19]],"date-time":"2021-10-19T00:00:00Z","timestamp":1634601600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100007109","name":"Universit\u00e0 degli Studi di Ferrara","doi-asserted-by":"publisher","award":["62040","0039804"],"award-info":[{"award-number":["62040","0039804"]}],"id":[{"id":"10.13039\/501100007109","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Birth Defects Research"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>The medial and maxillary aspects of the upper lip originate at separate embryonic stages and therefore may experience different maternal exposure patterns which may affect methylation. Based on this hypothesis, we investigated the level of methylation of the methylene tetrahydrofolate reductase promoter gene (m<jats:italic>MTHFR<\/jats:italic>) in tissues from cleft lip, and m<jats:italic>MTHFR<\/jats:italic> levels by <jats:italic>MTHFR<\/jats:italic> c.677C\u2009&gt;\u2009T genotype. We further investigated whether m<jats:italic>MTHFR<\/jats:italic> mitigates the effect of smoking on long interspersed nuclear element (LINE\u20101) methylation in these tissues.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>DNA extracted from medial and lateral tissues of 26 infants with nonsyndromic cleft lip with or without cleft palate (nsCL\/P) was bisulfite converted and m<jats:italic>MTHFR<\/jats:italic> was measured on a pyrosequenser. LINE\u20101 methylation and <jats:italic>MTHFR<\/jats:italic> c.677C\u2009&gt;\u2009T genotype data were obtained in our previous study.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>There was no substantial difference in m<jats:italic>MTHFR<\/jats:italic> (<jats:italic>p<\/jats:italic>\u00a0=\u00a0.733) and LINE\u20101 (<jats:italic>p<\/jats:italic>\u00a0=\u00a0.148) between the two tissues. m<jats:italic>MTHFR<\/jats:italic> was not influenced by <jats:italic>MTHFR<\/jats:italic> c.677C\u2009&gt;\u2009T genotype, but there was suggestive evidence that the difference was larger among infants exposed to maternal smoking compared to nonexposed. LINE\u20101 methylation differences were significant (<jats:italic>p<\/jats:italic>\u00a0=\u00a0.025) in infants born to nonsmoking mothers, but this was not apparent (<jats:italic>p<\/jats:italic>\u00a0=\u00a0.872) in infants born to mothers who smoked. Our Pearson's correlation analysis suggested a weak inverse association between m<jats:italic>MTHFR<\/jats:italic> and LINE\u20101 (<jats:italic>r<\/jats:italic>\u00a0=\u00a0\u2212.179, <jats:italic>p<\/jats:italic>\u00a0=\u00a0.381).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our preliminary observation of differences in patterns of m<jats:italic>MTHFR<\/jats:italic> levels in lip tissue suggests the interplay of gene and environment in the establishment of methylation in tissues at both sides of cleft lip. This requires investigation in a larger cohort, integrated with metabolic assessment.<\/jats:p><\/jats:sec>","DOI":"10.1002\/bdr2.1959","type":"journal-article","created":{"date-parts":[[2021,10,21]],"date-time":"2021-10-21T11:45:06Z","timestamp":1634816706000},"page":"1463-1469","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<scp><i>MTHFR<\/i><\/scp> promoter methylation might mitigate the effect of smoking at the level of <scp>LINE<\/scp>\u20101 in cleft lip tissues: A preliminary study"],"prefix":"10.1002","volume":"113","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4365-2749","authenticated-orcid":false,"given":"Mohammad Faisal J.","family":"Khan","sequence":"first","affiliation":[{"name":"Department of Neuroscience and Rehabilitation, Section of Medical Biochemistry, Molecular Biology and Genetics University of Ferrara  Ferrara 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Regional Centre for Orofacial Clefts and Craniofacial Anomalies, Department of Cranio\u2010Maxillo\u2010Facial Surgery San Paolo Hospital, University of Milan  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria C.","family":"Meazzini","sequence":"additional","affiliation":[{"name":"Smile House, Operation Smile, Regional Centre for Orofacial Clefts and Craniofacial Anomalies, Department of Cranio\u2010Maxillo\u2010Facial Surgery San Paolo Hospital, University of Milan  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1448-9516","authenticated-orcid":false,"given":"Michele","family":"Rubini","sequence":"additional","affiliation":[{"name":"Department of Neuroscience and Rehabilitation, Section of Medical Biochemistry, Molecular Biology and Genetics University of Ferrara  Ferrara 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