成纤维细胞生长因子1（FGF1）、叉头框E1（FOXE1）和金属蛋白酶组织抑制因子2（TIMP2）基因的变异与非综合征性唇裂伴或不伴腭裂有关。

Variation in FGF1, FOXE1, and TIMP2 genes is associated with nonsyndromic cleft lip with or without cleft palate.

作者信息

Nikopensius Tiit, Kempa Inga, Ambrozaitytė Laima, Jagomägi Triin, Saag Mare, Matulevičienė Aušra, Utkus Algirdas, Krjutškov Kaarel, Tammekivi Veronika, Piekuse Linda, Akota Ilze, Barkane Biruta, Krumina Astrida, Klovins Janis, Lace Baiba, Kučinskas Vaidutis, Metspalu Andres

机构信息

Institute of Molecular and Cell Biology, University of Tartu, Estonia.

出版信息

Birth Defects Res A Clin Mol Teratol. 2011 Apr;91(4):218-25. doi: 10.1002/bdra.20791. Epub 2011 Apr 1.

DOI:10.1002/bdra.20791

PMID:21462296

Abstract

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.

摘要

背景

非综合征性唇裂伴或不伴腭裂（CL/P）是一种常见的复杂出生缺陷，由多个基因与环境因素相互作用引起。

方法

在一个由来自爱沙尼亚、拉脱维亚和立陶宛人群的300例患者及606例对照组成的腭裂样本中，对40个与口面部裂隙相关的候选基因中的587个单核苷酸多态性进行了与CL/P的关联性检测。

结果

在病例对照比较中，FGF1基因rs34010的次要等位基因（p = 4.56 × 10(-4)）、WNT9B基因rs4968282（p = 0.0013）以及FOXE1基因rs7860144（p = 0.0021）与CL/P风险降低相关。FGF1、FOXE1和TIMP2的多个单倍型以及WNT9B、PVRL2和LHX8的单倍型与CL/P相关。在FGF1基因中发现保护单倍型rs250092/rs34010 GT的关联性最强（p = 5.01 × 10(-4)）。在COL2A1和WNT3基因之间观察到最强的上位相互作用。