Strong Association of Variants around FOXE1 and Orofacial Clefting

KU Ludwig, AC Bohmer, M Rubini, PA Mossey, S Herms, S Nowak, H Reutter, MA Alblas, B Lippke, S Barth, M Paredes-Zenteno, SG Munoz-Jimenez, R Ortiz-Lopez, T Kreusch, A Hemprich, M Martini, B Braumann, Agnes Jager, B Potzsch, A MolloyB Peterlin, P Hoffmann, MM Nothen, A Rojas-Martinez, M Knapp, Régine Steegers - Theunissen, E Mangold

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41 Citations (Scopus)


Nonsyndromic orofacial clefting (nsOFC) is a common, complex congenital disorder. The most frequent forms are nonsyndromic cleft lip with or without cleft palate (nsCL/P) and nonsyndromic cleft palate only (nsCPO). Although they are generally considered distinct entities, a recent study has implicated a region around the FOXE1 gene in both nsCL/P and nsCPO. To investigate this hypothesis, we analyzed the 2 most strongly associated markers (rs3758249 and rs4460498) in 2 independent samples of differing ethnicities: Central European (949 nsCL/P cases, 155 nsCPO cases, 1163 controls) and Mayan Mesoamerican (156 nsCL/P cases, 10 nsCPO cases, 338 controls). While highly significant associations for both single-nucleotide polymorphisms were obtained in nsCL/P (rs4460498: p(Europe) = 6.50 x 10(-06), p(Mayan) = .0151; rs3758249: p(Europe) = 2.41 x 10(-05), p(Mayan) = .0299), no association was found in nsCPO (p > .05). Genotyping of rs4460498 in 472 independent European trios revealed significant associations for nsCL/P (p = .016) and nsCPO (p = .043). A meta-analysis of all data revealed a genomewide significant result for nsCL/P (p = 1.31 x 10(-08)), which became more significant when nsCPO cases were added (p(nsOFC) = 1.56 x 10(-09)). These results strongly support the FOXE1 locus as a risk factor for nsOFC. With the data of the initial study, there is now considerable evidence that this locus is the first conclusive risk factor shared between nsCL/P and nsCPO.
Original languageUndefined/Unknown
Pages (from-to)376-381
Number of pages6
JournalJournal of Dental Research
Issue number4
Publication statusPublished - 2014

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  • EMC MGC-02-52-01-A

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