Vijayan V, Ummer R, Weber R, Silva R, Letra A
1 University of Texas Health Science Center at Houston School of Public Health, Houston, TX, USA.
2 University of Texas Health Science Center School of Dentistry, Houston, TX, USA.
Cleft Palate Craniofac J. 2018 Mar;55(3):335-341. doi: 10.1177/1055665617732782. Epub 2017 Dec 14.
Nonsyndromic cleft lip with or without cleft palate (NSCL±P) is a common craniofacial anomaly with multifactorial etiology. Evidence suggests that variations in WNT pathway genes contribute to an increased susceptibility to NSCL±P. The aim of this study was to investigate the association of AXIN1, APC, CTNNB1, DVL2, and GSK3β gene variants with NSCL±P in a case-control data set from Brazil.
471 individuals with NSCL±P and 504 unrelated control individuals of Caucasian ethnicity.
Twenty single-nucleotide polymorphisms (SNPs) in/nearby AXIN1, APC, CTNNB1, DVL2, and GSK3B genes were genotyped using Taqman chemistry in a Viia7 sequence detection instrument. Genotype, allele, and haplotype frequencies were compared among NSCL±P patients and controls using Fisher exact test, implemented in PLINK software. The level of significance was established at P ≤.002 under Bonferroni correction. In silico analysis of SNP function was assessed using MirSNP database.
Significant association was found between GSK3B rs13314595 genotypes and NSCL±P ( P = .0006). Additionally, nominal associations were found between DVL2 (rs35594616) and APC (rs448475) with NSCL±P ( P = .02 and P = .03, respectively). SNP haplotypes for GSK3B and APC genes showed nominal associations with NSCL±P ( P < .05). In silico analysis predicted that APC rs448475 harbors a binding site for the microRNA miR-617 and that the switch from a G allele to C allele enhances binding, whereas DVL2 rs35594616 did not appear to harbor microRNA-binding sites.
This study shows for the first time the association between GSK3B and NSCL±P and confirms the role of additional WNT pathway genes as candidates for NSCL±P.
非综合征性唇裂伴或不伴腭裂（NSCL±P）是一种常见的颅面畸形，病因多因素。有证据表明，WNT信号通路基因的变异会增加患NSCL±P的易感性。本研究的目的是在巴西的一个病例对照数据集中，调查AXIN1、APC、CTNNB1、DVL2和GSK3β基因变异与NSCL±P之间的关联。
471例NSCL±P患者和504名无血缘关系的白种人对照个体。
使用Taqman化学方法在Viia7序列检测仪器中对AXIN1、APC、CTNNB1、DVL2和GSK3B基因内/附近的20个单核苷酸多态性（SNP）进行基因分型。使用PLINK软件中的Fisher精确检验比较NSCL±P患者和对照之间的基因型、等位基因和单倍型频率。在Bonferroni校正下，显著性水平设定为P≤0.002。使用MirSNP数据库对SNP功能进行计算机模拟分析。
发现GSK3B rs13314595基因型与NSCL±P之间存在显著关联（P = 0.0006）。此外，还发现DVL2（rs35594616）和APC（rs448475）与NSCL±P之间存在名义上的关联（分别为P = 0.02和P = 0.03）。GSK3B和APC基因的SNP单倍型与NSCL±P存在名义上的关联（P < 0.05）。计算机模拟分析预测，APC rs448475含有微小RNA miR-617的结合位点，从G等位基因转换为C等位基因会增强结合，而DVL2 rs35594616似乎不含有微小RNA结合位点。
本研究首次表明GSK3B与NSCL±P之间的关联，并证实了其他WNT信号通路基因作为NSCL±P候选基因的作用。
