Institute for Research in Dental Sciences, School of Dentistry, Universidad de Chile, Santiago, Chile.
Research Centre in Dental Sciences (CICO), Dental School, Universidad de La Frontera, Temuco, Chile.
Oral Dis. 2020 Jan;26(1):159-165. doi: 10.1111/odi.13229. Epub 2019 Nov 26.
To assess the association between polymorphic variants from SHMT1 and MTHFS genes, involved in the cytoplasmic futile folate cycle, and the risk of nonsyndromic cleft lip with or without cleft palate (NSCL/P) in the Chilean population.
In a sample of 139 Chilean NSCL/P cases and 278 controls, we obtained the genotypes for nine variants of SHMT1 and MTHFS and the association between them and the phenotype was evaluated using odds ratios (OR) in additive (allele), dominant, and recessive models.
After correction for multiple comparisons, only the variant rs1979277 (G > A; p.Leu474Phe) from SHMT1 showed a significant and protective effect for additive (OR 0.60; 95% CI 0.42-0.86; p = .0054, q = 0.0488) and dominant models (OR 0.48; 95% CI 0.29-0.75; p = .0009; q = 0.0081). Our bioinformatic prediction plus functional evidence from previous reports demonstrate that the A allele for this missense variant decreases the enzymatic activity.
Owing to the rs1979277 A allele, which reduces the cytoplasmic SHMT activity and has a higher frequency in controls than in NSCL/P cases, we hypothesized that a low enzyme activity may increase the cytoplasmic concentration of folates and, therefore, explain the protective role against OFCs.
评估参与细胞质无效叶酸循环的 SHMT1 和 MTHFS 基因多态性变异与智利人群非综合征性唇裂伴或不伴腭裂（NSCL/P）风险之间的关联。
在 139 例智利 NSCL/P 病例和 278 例对照的样本中，我们获得了 9 种 SHMT1 和 MTHFS 变体的基因型，并使用加性（等位基因）、显性和隐性模型评估了它们与表型之间的关联。
经过多次比较校正后，仅来自 SHMT1 的变体 rs1979277（G>A；p.Leu474Phe）在加性（OR 0.60；95%CI 0.42-0.86；p=0.0054，q=0.0488）和显性模型（OR 0.48；95%CI 0.29-0.75；p=0.0009；q=0.0081）中显示出显著的保护作用。我们的生物信息学预测加上先前报道的功能证据表明，这种错义变体的 A 等位基因降低了酶活性。
由于 rs1979277 的 A 等位基因降低了细胞质 SHMT 活性，并且在对照组中的频率高于 NSCL/P 病例，我们假设低酶活性可能会增加细胞质中叶酸的浓度，从而解释其对 OFCs 的保护作用。
