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

<jats:title>Abstract</jats:title><jats:sec><jats:title>Objective</jats:title><jats:p>To assess the association between polymorphic variants from <jats:italic>SHMT1</jats:italic> and <jats:italic>MTHFS</jats:italic> 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.</jats:p></jats:sec><jats:sec><jats:title>Subjects and Methods</jats:title><jats:p>In a sample of 139 Chilean NSCL/P cases and 278 controls, we obtained the genotypes for nine variants of <jats:italic>SHMT1</jats:italic> and <jats:italic>MTHFS</jats:italic> and the association between them and the phenotype was evaluated using odds ratios (OR) in additive (allele), dominant, and recessive models.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>After correction for multiple comparisons, only the variant rs1979277 (G > A; p.Leu474Phe) from <jats:italic>SHMT1</jats:italic> showed a significant and protective effect for additive (OR 0.60; 95% CI 0.42–0.86; <jats:italic>p</jats:italic> = .0054, <jats:italic>q</jats:italic> = 0.0488) and dominant models (OR 0.48; 95% CI 0.29–0.75; <jats:italic>p</jats:italic> = .0009; <jats:italic>q</jats:italic> = 0.0081). Our bioinformatic prediction plus functional evidence from previous reports demonstrate that the A allele for this missense variant decreases the enzymatic activity.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>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.</jats:p></jats:sec>