A SHMT1 variant decreases the risk of nonsyndromic cleft lip with or without cleft palate in Chile

Objective: 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.

Subjects and methods: 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.

Results: 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.

Conclusions: 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.