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

2010; Wiley; Volume: 88; Issue: 9 Linguagem: Inglês

10.1002/bdra.20700

2472-1727

Tiit Nikopensius, Triin Jagomägi, Kaarel Krjutškov, Veronika Tammekivi, Mare Saag, Inga Prane, Linda Gailīte, Ilze Akota, Biruta Barkāne, Astrīda Krūmiņa, Laima Ambrozaitytė, Aušra Matulevičienė, Zita Aušrelė Kučinskienė, Baiba Lāce, Vaidutis Kučinskas, Andres Metspalu,

Urological Disorders and Treatments

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 CLPTM1 were 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. Birth Defects Research (Part A), 2010. © 2010 Wiley‐Liss, Inc.