Preliminary Analysis of the Nonsynonymous Polymorphism rs17563 in BMP4 Gene in Brazilian Population Suggests Protection for Nonsyndromic Cleft Lip and Palate

Abstract

Cleft lip with or without palate (CL±P) is common congenital anomalies in humans. Experimental evidence has demonstrated that bone morphogenetic protein 4 gene (Bmp4) is involved in the etiology of CL±P in animal models. The nonsynonymous polymorphism rs17563 T>C (p.V152A) in the BMP4 gene has been associated to the risk of nonsyndromic CL±P in Chinese population and microforms from different ethnic backgrounds. The aim of this study was to investigate the role of BMP4 gene in CL±P in Brazilian sample using genetic association approach. Our sample was composed by 123 patients with nonsyndromic CL±P and 246 controls, in which absence of CL±P was confirmed in 3 generations. The rs17563 polymorphism was genotyped by PCR-RFLP technique. Logistic regression was performed to evaluate allele and genotype association. Our data showed statistical power to detect association (86.83%) in this sample. Logistic regression results showed significant association between C allele and CL±P (P = 0.00018, OR = 0.40, and 95% CI = 0.25–0.65), as well as CC genotype and CL±P (P = 0.00018, OR = 0.35, and 95% CI = 0.19–0.66). So, there is a strong association between nonsyndromic CL±P and BMP4 rs17563 polymorphism in our sample and the C allele had a protective effect against the occurrence of nonsyndromic CL±P.

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

“…The SNP rs1801133 in MTHFR was evaluated in three studies (de Aguiar et al, ; Gaspar et al, ), with two of them finding significant odds for the presence of the T allele in NSCL ± P. The pooled OR was 1.20 (95% CI: 1.05–1.37, p = .007), confirming that the T is a risk allele for NSCL ± P (Figure d). The variant C allele in BMP4 rs17563 was significantly associated with a decreased risk for NSCL ± P in the original studies (Antunes et al, ; Araújo et al, ) and in this meta‐analysis (Figure e). The pooled OR for the C allele was 0.68 (95% CI: 0.51–0.90, p = .008).…”

“…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, ;).…”

A multicentric association study between 39 genes and nonsyndromic cleft lip and palate in a Brazilian population

“…(IRF6) (Rojas-Martinez et al, 2010), bone morphogenetic protein 4 (BMP4) , Araujo et al, 2012, jagged 2 (JAG2) (Vieira et al, 2005), ventral anterior homeobox 1 (VAX1) (Butali et al, 2013) anomalies have been associated with oral cleft (Shi et al, 2009). …”

Joint Testing of Genotypic and Gene-Environment Interaction Identified Novel Association for BMP4 with Non-Syndromic CL/P in an Asian Population Using Data from an International Cleft Consortium

“…The Bone Morphogenetic Protein 4 gene ( BMP4 ) on chromosome 14q22-q23 is one of the most promising candidate genes for NSCL/P, with evidence shown in animal experiments [17] – [20] , genome-wide linkage studies [21] , [22] , a candidate gene sequencing study [23] and several candidate gene association studies [24] – [29] , although there is inconsistency among candidate gene association studies and lack of support from published GWAS reports [6] – [8] , [ 30] .…”