title: Genetic variants in COL2A1, COL11A2, and IRF6 contribute risk to nonsyndromic cleft palate.
abstract: BACKGROUND
  Orofacial clefts are among the most common birth defects with a strong genetic component. Nonsyndromic cleft palate (NSCP) is a complex malformation determined by the interaction between multiple genes and environmental risk factors.
  
  
  METHODS
  We conducted a case-control association study to investigate the role of 40 candidate genes in predisposition to orofacial clefting. Five hundred ninety-one haplotype tagging single nucleotide polymorphism (tagSNPs) were genotyped in a clefting sample from the Baltic region, composed of 104 patients with nonsyndromic cleft palate and 606 controls from an Estonian, Latvian, and Lithuanian population.
  
  
  RESULTS
  In case-control comparisons, the minor alleles of IRF6 rs17389541 (p = 5.45 × 10(-4)) and COL2A1 rs1793949 (p = 7.26 × 10(-4)) were associated with increased risk of NSCP. Multiple haplotypes in COL2A1 and COL11A2 and haplotypes in WNT3, FGFR1, and CLPTM1were associated with NSCP. The strongest associations were found for IRF6 haplotype rs17389541/rs9430018 GT (p = 2.23 × 10(-4)) and COL2A1 haplotype rs12822608/rs6823 GC (p = 3.68 × 10(-4)). The strongest epistatic interactions were observed between MSX1 and BMP2, FGF1 and PVRL2, and COL2A1 and FGF2 genes.
  
  
  CONCLUSIONS
  This study provides for the first time evidence of the implication of IRF6, COL2A1, and WNT3 in the occurrence of NSCP. It is likely that variation in cartilage collagen II and XI genes, IRF6, and the Wnt and FGF signaling pathway genes contributes susceptibility to nonsyndromic cleft palate in Northeastern European populations.
authors.affiliation: Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia. tiitn@ebc.ee
authors.forename: Tiit
authors.initials: T
authors.lastname: Nikopensius
authors.forename: Triin
authors.initials: T
authors.lastname: Jagomägi
authors.forename: Kaarel
authors.initials: K
authors.lastname: Krjutskov
authors.forename: Veronika
authors.initials: V
authors.lastname: Tammekivi
authors.forename: Mare
authors.initials: M
authors.lastname: Saag
authors.forename: Inga
authors.initials: I
authors.lastname: Prane
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: Laima
authors.initials: L
authors.lastname: Ambrozaityte
authors.forename: Ausra
authors.initials: A
authors.lastname: Matuleviciene
authors.forename: Zita Ausrele
authors.initials: ZA
authors.lastname: Kucinskiene
authors.forename: Baiba
authors.initials: B
authors.lastname: Lace
authors.forename: Vaidutis
authors.initials: V
authors.lastname: Kucinskas
authors.forename: Andres
authors.initials: A
authors.lastname: Metspalu
mesh_terms: D001454:Baltic States; D016022:Case-Control Studies; D002971:Cleft Lip / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics*; D024043:Collagen Type II / Q000235:genetics*; D024161:Collagen Type XI / Q000235:genetics*; D004843:Epistasis, Genetic; D005260:Female; D018507:Gene Expression Regulation, Developmental; D056726:Genetic Association Studies; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics
chemical_list: C499319:COL11A2 protein, human; C499177:COL2A1 protein, human; D024043:Collagen Type II; D024161:Collagen Type XI; D005819:Genetic Markers; C109803:IRF6 protein, human; D050835:Interferon Regulatory Factors