Genetic variants in COL2A1, COL11A2, and IRF6 contribute risk to nonsyndromic cleft palate

Tiit Nikopensius, Triin Jagomägi, Kaarel Krjutškov, Veronika Tammekivi, Mare Saag, Inga Prane, Linda Piekuse, Ilze Akota, Biruta Barkane, Astrida Krumina, Laima Ambrozaityte, Aušra Matulevičiene, Zita Aušrele Kučinskiene, Baiba Lace, Vaidutis Kučinskas, Andres Metspalu

Research output: Contribution to journalArticlepeer-review

37 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)748-756
Number of pages9
JournalBirth Defects Research Part A - Clinical and Molecular Teratology
Issue number9
Publication statusPublished - Sept 2010


  • APEX
  • Case-control association study
  • Genotyping
  • Nonsyndromic cleft palate
  • 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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