Variation in FGF1, FOXE1, and TIMP2genes is associated with nonsyndromic cleft lip with or without cleft palate.

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. Birth Defects Research(Part A), 2011. © 2011 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]