Salamanca Carlos, González-Hormazábal Patricio, Recabarren Andrea S, Recabarren Pamela A, Pantoja Roberto, Leiva Noemi, Pardo Rosa, Suazo José
Institute for Research in Dental Sciences, School of Dentistry, Universidad de Chile, Santiago, Chile.
Research Center in Dental Sciences (CICO), Dental School, Universidad de La Frontera, Santiago, Chile.
Pediatr Res. 2021 Mar;89(4):1020-1025. doi: 10.1038/s41390-020-0994-3. Epub 2020 Jun 3.
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.
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.
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.
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.
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.
S-腺苷甲硫氨酸（SAM）的可用性对于DNA甲基化至关重要，DNA甲基化是一种参与非综合征性唇裂伴或不伴腭裂（NSCL/P）表达的表观遗传机制。本研究的目的是评估智利人群中参与SAM合成的基因的单核苷酸多态性（SNP）与NSCL/P之间的关联。
对234例病例和309例对照进行基因分型，检测AHCY、MTR、MTRR和MAT2A基因中的18个SNP，并通过计算优势比（OR），基于加性（等位基因）、显性、隐性和单倍型模型评估它们与表型之间的关联。
MTR基因的三个内含子深处的SNP对NSCL/P表达具有保护作用：rs10925239（OR 0.68；p = 0.0032；q = 0.0192）、rs10925254（OR 0.66；p = 0.0018；q = 0.0162）和rs3768142（OR 0.66；p = 0.0015；q = 0.0162）。表达数据库中的注释表明，这三个SNP的保护性等位基因与MTR表达的降低相关，同时生物信息学工具预测其具有改变剪接位点的潜力。
这些MTR内含子SNP对NSCL/P的保护作用似乎与MTR酶表达的降低有关，从而调节SAM用于适当底物甲基化的可用性。然而，需要进行功能分析来证实我们的发现。
SAM合成途径的基因变异是与NSCL/P相关的因素。本文为智利人群中NSCL/P的叶酸相关基因增添了新证据。其影响在于为遗传咨询提供潜在的新标记。
