The functional EGF+61 polymorphism and nonsyndromic oral clefts susceptibility in a Brazilian population

Abstract

Nonsyndromic oral clefts are considered a problem of public health in Brazil, presenting a multifactorial etiology that involves genetic and environmental components, such as maternal alcohol consumption. Several candidate genes have been investigated to identify some association with nonsyndromic clefts risk. The epidermal growth factor (EGF) gene is implicated in the normal craniofacial development and its functional +61 A>G polymorphism has been related to cancer susceptibility. It has been suggested that cancer and oral clefts may share the same molecular pathways. Objective Our goal was to evaluate the association between the EGF+61 A>G polymorphism and nonsyndromic oral clefts susceptibility.Material and Methods The case-control study included 218 cleft cases and 253 controls from Brazil. The control group was comprised of individuals without congenital malformations, dental anomalies and family history of clefts. The cleft phenotypes and subphenotypes were determined based on clinical examination. Genomic DNA was extracted from oral mucosa cells obtained by mouthwash. The EGF+61 A>G polymorphism genotype was determined by polymerase chain reaction-restriction fragment length polymorphism.Results We noticed the association between maternal alcohol consumption during pregnancy and cleft occurrence. The A allele and AA genotype were over-represented in cleft cases compared with control group when we considered the bilateral cleft lip with or without cleft palate (CL±P) cases, cleft cases with tooth agenesis and cleft cases presenting family history of cleft, but the differences were not statistically significant. Contradictorily, the G allele was higher in cleft palate only (CP) cases than in control group, showing a borderline p value. Comparing the different cleft phenotypes, we observed statistical differences between CP and CL±P cases. Our data suggest the EGF+61 A>G polymorphism was not related with nonsyndromic oral clefts susceptibility in a Brazilian population, but supported the different genetic background between CL±P and CP. Moreover, we confirmed the potential effect of maternal alcohol intake on cleft risk in our population.

Potential genetic markers for nonsyndromic oral clefts in the Brazilian population: A systematic review and meta‐analysis

“…In the second phase, the full‐text review was then conducted on the 71 first‐phase selected citations, which lead to the exclusion of 22 studies. In the end of the two phases, 49 studies fulfilled the inclusion criteria (Antunes et al, ; Araújo et al, ; Araujo et al, ; Bagordakis et al, ; Bezerra et al, ; Brandalize et al, ; Brito, Bassi, & Masotti, ; Brito et al, ; Bufalino et al, ; Cardoso et al, ; Choi et al, ; da Silva, Ribeiro, Cooper, Marazita, & Moretti‐Ferreira, ; de Aguiar et al, ; de Aquino et al, a,b; de Souza et al, ; do Rego Borges et al, ; Ehlers Bertoja, Sampaio Alho, De França, Menegotto, & Miriam Robinson, ; Falagan‐Lotsch et al, ; Filézio et al, ; Fontoura, Silva, Granjeiro, & Letra, ; Gaspar et al, ; Jehee et al, ; Küchler et al, ; Letra, Menezes, Granjeiro, & Vieira, ; Letra, Silva, & Menezes, ; Letra et al, a,b; Machado et al, a,b, ; Menezes, Letra, Ruff, Granjeiro, & Vieira, ; Menezes et al, ; Messetti et al, ; Paranaíba et al, ; Passos‐Bueno et al, ; Sabóia et al, ; Souza, Kowalski, Collares, & Félix, ; Souza, Kowalski, Vanz, Giugliani, & Félix, ; Waltrick‐Zambuzzi et al, ; Zucchero et al, ), but only 11 articles were used in the meta‐analysis (Antunes et al, ; Araújo et al, ; Bagordakis et al, ; Brito et al, ; de Aguiar et al, ; do Rego Borges et al, ; Fontoura et al, ; Gaspar et al, ; Paranaíba et al, ;).…”

MicroRNA Profiling during Craniofacial Development: Potential Roles for Mir23b and Mir133b

“…Interestingly, both EGF and FGF signaling have been implicated in craniofacial development. Mutations in EGF signaling have been implicated in human clefting (Falagan-Lotsch et al, 2015 ) and cranial suture formation in mice (Rawlins et al, 2008 ). More roles have been ascribed for FGF signaling in craniofacial development, with FGFR1 specifically linked to skeletal dysplasias and craniosynostosis in both humans and mice, suggesting a mechanism by which Mir133b may regulate craniofacial development (Moosa and Wollnik, 2016 ).…”

Nucleotide variants of the NAT2 and EGF61 genes in patients in Northern China with nonsyndromic cleft lip with or without cleft palate

“…Individuals with the GG or AG genotype exhibited higher EGF production in vitro than individuals with the AA genotype, and homozygosity of the G allele was shown to be associated with the risk of developing malignant melanoma and several other malignancies, including gastric cancer [ 26 ] and glioma. [ 27 ] Furthermore, an association between rs4444903 and NSCL/P was not identified by Falagan-Lotsch et al, [ 14 ] and rs4444903 was not shown to be associated with NSCL/P in a Brazilian population. In the present research, we found that the SNP rs4444903 was significantly associated with NSCL/P ( P = .012), and the EGF 61 (rs4444903) gene was related to a decreased risk of NSCL/P.…”

“…We selected 2 single-nucleotide polymorphisms (SNPs), rs1799929 in NAT2 and rs4444903 in EGF61, according to the research of Santos et al [ 13 ] and Falagan-Lotsch et al [ 14 ] .…”

“…Meanwhile, Falagan-Lotsch et al [ 14 ] have provided evidence that the EGF61 A>G polymorphism was not related to susceptibility to nonsyndromic oral clefts in a Brazilian population, but supported a different genetic background between CL ± P and CP.…”