Strong association of variants around FOXE1 and orofacial clefting

K. U. Ludwig, A. C. Böhmer, M. Rubini, P. A. Mossey, S. Herms, S. Nowak, H. Reutter, M. A. Alblas, B. Lippke, S. Barth, M. Paredes-Zenteno, S. G. Muñoz-Jimenez, R. Ortiz-Lopez, T. Kreusch, A. Hemprich, M. Martini, B. Braumann, A. Jäger, B. Pötzsch, A. MolloyB. Peterlin, P. Hoffmann, M. M. Nöthen, A. Rojas-Martinez, M. Knapp, R. P. Steegers-Theunissen, E. Mangold (Lead / Corresponding author)

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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: pEurope = 6.50 × 10-06, pMayan =.0151; rs3758249: pEurope = 2.41 × 10-05, pMayan =.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 × 10-08), which became more significant when nsCPO cases were added (pnsOFC = 1.56 × 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 languageEnglish
Pages (from-to)376-381
Number of pages6
JournalJournal of Dental Research
Issue number4
Early online date21 Feb 2014
Publication statusPublished - Apr 2014


  • cleft lip
  • cleft palate
  • genetic model
  • case-control
  • association study
  • single-nucleotide ploymorphism


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