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
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SAM synthesis pathway genetic variants are factors associated to NSCL/P.
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This article adds new evidence for folate related genes in NSCL/P in Chile.
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Its impact is to contribute with potential new markers for genetic counseling.
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Acknowledgements
We thank the patients, their families, and healthy individuals who voluntarily cooperated with us, and the staff members of all cleft children rehabilitation centers and blood banks. We also thank the University of Chile BioBank (BTUCH) staff members for their fundamental work. This study was supported by the Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT, Chile) Grant #1170805.
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C.S. made substantial contributions to conception and design, analysis and interpretation of data, drafting, revising, and approved the final version of the manuscript. P.G-H. made substantial contributions to conception, analysis and interpretation of data, drafting, revising, and approved the final version of the manuscript. A.S.R. made substantial contributions to acquisition of data, drafting, revising, and approved the final version of the manuscript. P.A.R. made substantial contributions to acquisition of data, drafting, revising, and approved the final version of the manuscript. R.P. made substantial contributions to the acquisition of data, drafting, revising, and approved the final version of the manuscript. N.L. made substantial contributions to acquisition of data, drafting, revising, and approved the final version of the manuscript. R.P. made substantial contributions to acquisition of data, drafting, revising, and approved the final version of the manuscript. J.S. made substantial contributions to conception and design, acquisition, analysis and interpretation of data, drafting, revising, and approved the final version of the manuscript.
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Informed consent for all participants was required, which was approved by the Institutional Review Board of the Faculty of Dentistry, Universidad de Chile (Protocol #2017/07).
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Salamanca, C., González-Hormazábal, P., Recabarren, A.S. et al. Genetic variants in S-adenosyl-methionine synthesis pathway and nonsyndromic cleft lip with or without cleft palate in Chile. Pediatr Res 89, 1020–1025 (2021). https://doi.org/10.1038/s41390-020-0994-3
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DOI: https://doi.org/10.1038/s41390-020-0994-3
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