Carlos Salamanca1,2,3, Patricio González-Hormazábal4, Andrea S Recabarren1, Pamela A Recabarren1, Roberto Pantoja5,6, Noemi Leiva7, Rosa Pardo8,9,10, José Suazo11. 1. Institute for Research in Dental Sciences, School of Dentistry, Universidad de Chile, Santiago, Chile. 2. Research Center in Dental Sciences (CICO), Dental School, Universidad de La Frontera, Santiago, Chile. 3. Universidad Adventista de Chile, Chillán, Chile. 4. Human Genetics Program, Institute of Biomedical Sciences, School of Medicine, Universidad de Chile, Santiago, Chile. 5. Unit of Oral and Maxillofacial Surgery, Hospital Clínico San Borja-Arriaran, Santiago, Chile. 6. Department of Oral and Maxillofacial Surgery, School of Dentistry, Universidad de Chile, Santiago, Chile. 7. Unit of Maxillofacial Malformations, School of Dentistry, Universidad de Chile, Santiago, Chile. 8. Section of Genetics, Hospital Clínico Universidad de Chile, Santiago, Chile. 9. Unit of Neonatology, Hospital Clínico Universidad de Chile, Santiago, Chile. 10. Unit of Genetics, Hospital Dr. Sótero del Río, Santiago, Chile. 11. Institute for Research in Dental Sciences, School of Dentistry, Universidad de Chile, Santiago, Chile. jsuazo@odontologia.uchile.cl.
Abstract
BACKGROUND: The S-adenosyl-methionine (SAM) availability is crucial for DNA methylation, an epigenetic mechanism involved in nonsyndromic cleft lip with or without cleft palate (NSCL/P) expression. The aim of this study was to assess the association between single-nucleotide polymorphisms (SNPs) of genes involved in SAM synthesis and NSCL/P in a Chilean population. METHODS: In 234 cases and 309 controls, 18 SNPs in AHCY, MTR, MTRR, and MAT2A were genotyped, and the association between them and the phenotype was evaluated based on additive (allele), dominant, recessive and haplotype models, by odds ratio (OR) computing. RESULTS: Three deep intronic SNPs of MTR showed a protective effect on NSCL/P expression: rs10925239 (OR 0.68; p = 0.0032; q = 0.0192), rs10925254 (OR 0.66; p = 0.0018; q = 0.0162), and rs3768142 (OR 0.66; p = 0.0015; q = 0.0162). Annotations in expression database demonstrate that the protective allele of the three SNPs is associated with a reduction of MTR expression summed to the prediction by bioinformatic tools of its potentiality to modify splicing sites. CONCLUSIONS: The protective effect against NSCL/P of these intronic MTR SNPs seems to be related to a decrease in MTR enzyme expression, modulating the SAM availability for proper substrate methylation. However, functional analyses are necessary to confirm our findings. IMPACT: SAM synthesis pathway genetic variants are factors associated to NSCL/P. This article adds new evidence for folate related genes in NSCL/P in Chile. Its impact is to contribute with potential new markers for genetic counseling.
BACKGROUND: The S-adenosyl-methionine (SAM) availability is crucial for DNA methylation, an epigenetic mechanism involved in nonsyndromic cleft lip with or without cleft palate (NSCL/P) expression. The aim of this study was to assess the association between single-nucleotide polymorphisms (SNPs) of genes involved in SAM synthesis and NSCL/P in a Chilean population. METHODS: In 234 cases and 309 controls, 18 SNPs in AHCY, MTR, MTRR, and MAT2A were genotyped, and the association between them and the phenotype was evaluated based on additive (allele), dominant, recessive and haplotype models, by odds ratio (OR) computing. RESULTS: Three deep intronic SNPs of MTR showed a protective effect on NSCL/P expression: rs10925239 (OR 0.68; p = 0.0032; q = 0.0192), rs10925254 (OR 0.66; p = 0.0018; q = 0.0162), and rs3768142 (OR 0.66; p = 0.0015; q = 0.0162). Annotations in expression database demonstrate that the protective allele of the three SNPs is associated with a reduction of MTR expression summed to the prediction by bioinformatic tools of its potentiality to modify splicing sites. CONCLUSIONS: The protective effect against NSCL/P of these intronic MTR SNPs seems to be related to a decrease in MTR enzyme expression, modulating the SAM availability for proper substrate methylation. However, functional analyses are necessary to confirm our findings. IMPACT: SAM synthesis pathway genetic variants are factors associated to NSCL/P. This article adds new evidence for folate related genes in NSCL/P in Chile. Its impact is to contribute with potential new markers for genetic counseling.
Authors: Mohammad Faisal J Khan; Julian Little; Valentina Aleotti; Peter A Mossey; Régine P M Steegers-Theunissen; Luca Autelitano; Maria C Meazzini; Amin Ravaei; Michele Rubini Journal: Oral Dis Date: 2019-06-20 Impact factor: 3.511
Authors: George L Wehby; Dorthe Almind Pedersen; Jeffrey C Murray; Kaare Christensen Journal: BMC Health Serv Res Date: 2012-03-09 Impact factor: 2.655
Authors: Elizabeth J Leslie; Jenna C Carlson; John R Shaffer; Carmen J Buxó; Eduardo E Castilla; Kaare Christensen; Frederic W B Deleyiannis; Leigh L Field; Jacqueline T Hecht; Lina Moreno; Ieda M Orioli; Carmencita Padilla; Alexandre R Vieira; George L Wehby; Eleanor Feingold; Seth M Weinberg; Jeffrey C Murray; Mary L Marazita Journal: Am J Med Genet A Date: 2017-04-19 Impact factor: 2.578