ABSTRACT
OBJECTIVE: 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 GSK3ß gene variants with NSCL±P in a case-control data set from Brazil. PATIENTS: 471 individuals with NSCL±P and 504 unrelated control individuals of Caucasian ethnicity. DESIGN: 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. RESULTS: 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. CONCLUSION: 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.
Subject(s)
Cleft Lip/genetics , Cleft Palate/genetics , Glycogen Synthase Kinase 3 beta/genetics , Wnt Signaling Pathway/genetics , Adenomatous Polyposis Coli Protein/genetics , Alleles , Axin Protein/genetics , Brazil , Case-Control Studies , Dishevelled Proteins/genetics , Female , Gene Frequency , Genetic Predisposition to Disease , Genotype , Haplotypes , Humans , Male , Polymorphism, Single Nucleotide , beta Catenin/geneticsABSTRACT
Ductal plate malformation, a term given to intrahepatic bile ducts that retain the fetal configuration, is observed in some cases of biliary atresia. We examined 21 livers from patients with biliary atresia; ductal plate malformation occurred in 38% of cases, and its presence was predictive of poor clinical outcome (P =.04).