Variation in FGF1, FOXE1, and TIMP2genes is associated with nonsyndromic cleft lip with or without cleft palate

Tiit Nikopensius, Inga Kempa, Laima Ambrozaityte, Triin Jagomägi, Mare Saag, Aušra Matulevičiene, Algirdas Utkus, Kaarel Krjutškov, Veronika Tammekivi, Linda Piekuse, Ilze Akota, Biruta Barkane, Astrida Krumina, Janis Klovins, Baiba Lace, Vaidutis Kučinskas, Andres Metspalu

Research output: Contribution to journalArticlepeer-review

37 Citations (Scopus)


BACKGROUND: Nonsyndromic cleft lip with or without cleft palate (CL/P) is a common complex birth defect caused by the interaction between multiple genes and environmental factors. METHODS: Five hundred and eighty-seven single nucleotide polymorphisms in 40 candidate genes related to orofacial clefting were tested for association with CL/P in a clefting sample composed of 300 patients and 606 controls from Estonian, Latvian, and Lithuanian populations. RESULTS: In case-control comparisons, the minor alleles of FGF1 rs34010 (p = 4.56 × 10-4), WNT9B rs4968282 (p = 0.0013), and FOXE1 rs7860144 (p = 0.0021) were associated with a decreased risk of CL/P. Multiple haplotypes in FGF1, FOXE1, and TIMP2 and haplotypes in WNT9B, PVRL2, and LHX8 were associated with CL/P. The strongest association was found for protective haplotype rs250092/rs34010 GT in the FGF1 gene (p = 5.01 × 10-4). The strongest epistatic interaction was observed between the COL2A1 and WNT3 genes. CONCLUSIONS: Our results provide for the first time evidence implicating FGF1 in the occurrence of CL/P, and support TIMP2 and WNT9B as novel loci predisposing to CL/P. We have also replicated recently reported significant associations between variants in or near FOXE1 and CL/P. It is likely that variation in FOXE1, TIMP2, and the FGF and Wnt signaling pathway genes confers susceptibility to nonsyndromic CL/P in Northeastern European populations.

Original languageEnglish
Pages (from-to)218-225
Number of pages8
JournalBirth Defects Research Part A - Clinical and Molecular Teratology
Issue number4
Publication statusPublished - Apr 2011


  • APEX
  • Case-control association study
  • Cleft lip with or without cleft palate
  • Oral clefts
  • SNP

Field of Science*

  • 1.6 Biological sciences
  • 3.2 Clinical medicine

Publication Type*

  • 1.1. Scientific article indexed in Web of Science and/or Scopus database


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