Ethnic Differences in the Brazilian Population Influence the Impact of BMP4 Genetic Variants on Susceptibility of Nonsyndromic Orofacial Clefts

Lilianny Querino Rocha de Oliveira; Hellen Carolliny de Souza Nicolau; Daniella Reis Barbosa Martelli; Hercílio Martelli-Júnior; Rafaela Scariot; Ana Lúcia Carrinho Ayroza Rangel; Silvia Regina de Almeida Reis; Ricardo D Coletta; Renato Assis Machado

doi:10.1177/10556656231180086

Ethnic Differences in the Brazilian Population Influence the Impact of BMP4 Genetic Variants on Susceptibility of Nonsyndromic Orofacial Clefts

Cleft Palate Craniofac J. 2023 Jun 4:10556656231180086. doi: 10.1177/10556656231180086. Online ahead of print.

Affiliations

¹ Graduate Program in Oral Biology, School of Dentistry, University of Campinas, Piracicaba, São Paulo, Brazil.
² Stomatology Clinic, Dental School, State University of Montes Claros, Montes Claros, Minas Gerais, Brazil.
³ Center for Rehabilitation of Craniofacial Anomalies, Dental School, University of Professor Edson Antônio Velano, Alfenas, Minas Gerais, Brazil.
⁴ Department of Oral and Maxillofacial Surgery, School of Health Science, Federal University of Paraná, Curitiba, Brazil.
⁵ Center of Biological Sciences and of the Health, School of Dentistry, State University of Western Paraná, Cascavel, Paraná, Brazil.
⁶ Department of Basic Science, Bahiana School of Medicine and Public Health, Salvador, Bahia, Brazil.
⁷ Department of Oral Diagnosis, School of Dentistry, University of Campinas, Piracicaba, São Paulo, Brazil.

PMID: 37272066
DOI: 10.1177/10556656231180086

Abstract

Objective: The study evaluated the association of BMP4 tag-SNPs and SNP-SNP interactions involving genes active by BMP4 pathway during craniofacial development in the susceptibility of nonsyndromic orofacial clefts (NSOC) in the Brazilian population.

Design: Case-control study.

Setting: Brazilian Oral Cleft Group.

Participants: The study included 881 healthy controls and 800 patients with different types of NSOC: 232 with cleft lip only (NSCLO), 568 with cleft lip and palate (NSCLP), and 274 with cleft palate only (NSCPO).

Interventions: The genomic DNA was genotyped with allelic discrimination assays for five BMP4 tag-SNPs (rs11623717, rs17563, rs2071047, rs2761887 and rs4898820), and analyzed their allelic and genotypic associations using multiple logistic regression. The interactions of these variants with genes involved in the BMP4 signaling pathway, including FGFR1, GREM1, NOG, VAX1 and the 4p16.2 locus, were explored.

Main outcome measures: BMP4 variants in the NSOC risk.

Results: Although only nominal p values were identified when the whole sample was considered, subgroup analysis including the patients with high African genomic ancestry showed significant associations of rs2761887 with risk for nonsyndromic cleft lip with or without cleft palate (NSCL ± P)[(OR_hom: 2.16; 95% CI: 1.21-3.85; p = 0.01) and (OR_rec: 2.05; 95% CI: 1.21-3.47; p = 0.006)]. Thirteen significant SNP-SNP interactions involving BMP4 and the SNPs at FGFR1, GREM1, NOG and VAX1 and at locus 4p16.2 for increased risk of NSCL ± P were identified.

Conclusions: Our results demonstrate an increased risk of NSCL ± P in Brazilian individuals with enrichment of African ancestry in the presence of the BMP4 rs2762887 polymorphism, and reveal relevant genetic contribution of SNP-SNP epistatic interactions involving BMP4 variants to NSCL ± P risk.

Keywords: African ancestry; SNP-SNP interactions; bone morphogenetic protein 4; nonsyndromic orofacial clefts.