Camila Sane Viena1, Renato Assis Machado2, Darlene Camati Persuhn3, Hercílio Martelli-Júnior4,5, Alena Peixoto Medrado1, Ricardo D Coletta2, Silvia R A Reis1. 1. Basic Science Department, Area of Oral Pathology, Bahiana School of Medicine and Public Health, Salvador, Bahia, Brazil. 2. Department of Oral Diagnosis, School of Dentistry, University of Campinas, Piracicaba, São Paulo, Brazil. 3. Molecular Biology Department, Federal University of Paraíba, João Pessoa, Paraíba, Brazil. 4. Stomatology Clinic, Dental School, State University of Montes Claros, Montes Claros, Minas Gerais, Brazil. 5. Center for Rehabilitation of Craniofacial Anomalies, Dental School, University of José Rosário Vellano, Minas Gerais, Brazil.
Abstract
BACKGROUND: GREM1, which encodes Gremlin 1, an antagonist of bone morphogenic proteins with effects on proliferation and apoptosis, has been considered a candidate gene for nonsyndromic cleft lip with or without cleft palate (NSCL±P). In this study, we investigated potential associations of single nucleotide polymorphisms (SNP) in GREM1 and NSCL±P risk in the Brazilian population. Additionally, SNP-SNP interactions of GREM1 with previously reported rs1880646 variant in NTN1 (netrin 1), a gene also responsible for apoptotic phenotypes were verified. METHODS: Applying Taqman allelic discrimination assays, we evaluated the variants rs16969681, rs16969816, rs16969862, and rs1258763 in 325 case-parent trios and in 1,588 isolated samples in a case-control study. Allelic and genotypic analyses, as well as interaction tests assessing gene-environmental factor (GxE) and SNP-SNP interaction with rs1880646 variant in NTN1, were performed based on logistic regression analysis adjusted for the effects of gender and genomic ancestry proportions. RESULTS: The risk alleles of all SNP were undertransmitted in NSCL±P trios, though the case-control analysis confirmed only the association with rs16969862 alleles (OR: 0.78, 95% CI: 0.63-0.96, p = .02). The GxE interaction analysis revealed a significant interaction between maternal environmental contact with agrotoxics and rs16969816 (OR: 0.25, 95% CI: 0.08-0.74, p = .01), and pairwise interaction test with NTN1 rs1880646 yielded significant p values in the 1,000 permutation test for rs16969681, rs16969816, and rs16969862. CONCLUSION: The GREM1 is involved in the etiology of NSCL±P in the Brazilian population and reveal that the interaction between GREM1 and NTN1 may be related with the pathogenesis of this common craniofacial malformation.
BACKGROUND:GREM1, which encodes Gremlin 1, an antagonist of bone morphogenic proteins with effects on proliferation and apoptosis, has been considered a candidate gene for nonsyndromic cleft lip with or without cleft palate (NSCL±P). In this study, we investigated potential associations of single nucleotide polymorphisms (SNP) in GREM1 and NSCL±P risk in the Brazilian population. Additionally, SNP-SNP interactions of GREM1 with previously reported rs1880646 variant in NTN1 (netrin 1), a gene also responsible for apoptotic phenotypes were verified. METHODS: Applying Taqman allelic discrimination assays, we evaluated the variants rs16969681, rs16969816, rs16969862, and rs1258763 in 325 case-parent trios and in 1,588 isolated samples in a case-control study. Allelic and genotypic analyses, as well as interaction tests assessing gene-environmental factor (GxE) and SNP-SNP interaction with rs1880646 variant in NTN1, were performed based on logistic regression analysis adjusted for the effects of gender and genomic ancestry proportions. RESULTS: The risk alleles of all SNP were undertransmitted in NSCL±P trios, though the case-control analysis confirmed only the association with rs16969862 alleles (OR: 0.78, 95% CI: 0.63-0.96, p = .02). The GxE interaction analysis revealed a significant interaction between maternal environmental contact with agrotoxics and rs16969816 (OR: 0.25, 95% CI: 0.08-0.74, p = .01), and pairwise interaction test with NTN1rs1880646 yielded significant p values in the 1,000 permutation test for rs16969681, rs16969816, and rs16969862. CONCLUSION: The GREM1 is involved in the etiology of NSCL±P in the Brazilian population and reveal that the interaction between GREM1 and NTN1 may be related with the pathogenesis of this common craniofacial malformation.