TY - JOUR
T1 - Variation in FGF1, FOXE1, and TIMP2genes is associated with nonsyndromic cleft lip with or without cleft palate
AU - Nikopensius, Tiit
AU - Kempa, Inga
AU - Ambrozaityte, Laima
AU - Jagomägi, Triin
AU - Saag, Mare
AU - Matulevičiene, Aušra
AU - Utkus, Algirdas
AU - Krjutškov, Kaarel
AU - Tammekivi, Veronika
AU - Piekuse, Linda
AU - Akota, Ilze
AU - Barkane, Biruta
AU - Krumina, Astrida
AU - Klovins, Janis
AU - Lace, Baiba
AU - Kučinskas, Vaidutis
AU - Metspalu, Andres
PY - 2011/4
Y1 - 2011/4
N2 - 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.
AB - 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.
KW - APEX
KW - Case-control association study
KW - Cleft lip with or without cleft palate
KW - Oral clefts
KW - SNP
UR - http://www.scopus.com/inward/record.url?scp=79954539522&partnerID=8YFLogxK
UR - https://onlinelibrary.wiley.com/doi/pdf/10.1002/bdra.20791
U2 - 10.1002/bdra.20791
DO - 10.1002/bdra.20791
M3 - Article
C2 - 21462296
AN - SCOPUS:79954539522
SN - 1542-0752
VL - 91
SP - 218
EP - 225
JO - Birth Defects Research Part A - Clinical and Molecular Teratology
JF - Birth Defects Research Part A - Clinical and Molecular Teratology
IS - 4
ER -