Genetic variants in COL2A1, COL11A2, and IRF6 contribute risk to nonsyndromic cleft palate.
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.
Nikopensius
Tiit
T
Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia. tiitn@ebc.ee
Jagomägi
Triin
T
Krjutskov
Kaarel
K
Tammekivi
Veronika
V
Saag
Mare
M
Prane
Inga
I
Piekuse
Linda
L
Akota
Ilze
I
Barkane
Biruta
B
Krumina
Astrida
A
Ambrozaityte
Laima
L
Matuleviciene
Ausra
A
Kucinskiene
Zita Ausrele
ZA
Lace
Baiba
B
Kucinskas
Vaidutis
V
Metspalu
Andres
A
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
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