title: Variation in FGF1, FOXE1, and TIMP2 genes is associated with nonsyndromic cleft lip with or without cleft palate.
abstract: 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.
authors.affiliation: Institute of Molecular and Cell Biology, University of Tartu, Estonia. tiitn@ebc.ee
authors.forename: Tiit
authors.initials: T
authors.lastname: Nikopensius
authors.forename: Inga
authors.initials: I
authors.lastname: Kempa
authors.forename: Laima
authors.initials: L
authors.lastname: Ambrozaitytė
authors.forename: Triin
authors.initials: T
authors.lastname: Jagomägi
authors.forename: Mare
authors.initials: M
authors.lastname: Saag
authors.forename: Aušra
authors.initials: A
authors.lastname: Matulevičienė
authors.forename: Algirdas
authors.initials: A
authors.lastname: Utkus
authors.forename: Kaarel
authors.initials: K
authors.lastname: Krjutškov
authors.forename: Veronika
authors.initials: V
authors.lastname: Tammekivi
authors.forename: Linda
authors.initials: L
authors.lastname: Piekuse
authors.forename: Ilze
authors.initials: I
authors.lastname: Akota
authors.forename: Biruta
authors.initials: B
authors.lastname: Barkane
authors.forename: Astrida
authors.initials: A
authors.lastname: Krumina
authors.forename: Janis
authors.initials: J
authors.lastname: Klovins
authors.forename: Baiba
authors.initials: B
authors.lastname: Lace
authors.forename: Vaidutis
authors.initials: V
authors.lastname: Kučinskas
authors.forename: Andres
authors.initials: A
authors.lastname: Metspalu
mesh_terms: D016022:Case-Control Studies; D015815:Cell Adhesion Molecules / Q000235:genetics; D002971:Cleft Lip / Q000453:epidemiology / Q000235:genetics*; D002972:Cleft Palate / Q000453:epidemiology / Q000235:genetics*; D004843:Epistasis, Genetic; D004957:Estonia / Q000453:epidemiology; D005260:Female; D016220:Fibroblast Growth Factor 1 / Q000235:genetics*; D051858:Forkhead Transcription Factors / Q000235:genetics*; D056426:Genetic Loci; D006239:Haplotypes; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D060850:LIM-Homeodomain Proteins; D007844:Latvia / Q000453:epidemiology; D008097:Lithuania / Q000453:epidemiology; D008297:Male; D000075983:Nectins; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics*; D014157:Transcription Factors; D051153:Wnt Proteins / Q000235:genetics
chemical_list: D015815:Cell Adhesion Molecules; C106894:FOXE1 protein, human; D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins; C112960:LIM homeobox protein 8; D060850:LIM-Homeodomain Proteins; D000075983:Nectins; D014157:Transcription Factors; C449090:WNT9B protein, human; D051153:Wnt Proteins; D016220:Fibroblast Growth Factor 1; D019716:Tissue Inhibitor of Metalloproteinase-2